Feliza Mirasol is the science editor for 

Feliza Mirasol

The European Medicines Agency (EMA) has granted orphan designation to rilzabrutinib, an investigational oral Bruton’s tyrosine kinase (BTK) inhibitor from Sanofi (1). The designation applies to the treatment of IgG4-related disease (IgG4-RD). Orphan designation is granted to therapies targeting rare, serious, or debilitating conditions affecting no more than five in 10,000 people in the European Union, underscoring the unmet medical need in this patient population (1).

Clinical data support potential in rare immune-mediated disorders

EMA’s decision is based on results from a Phase II clinical trial (NCT04520451) in which patients received rilzabrutinib for 52 weeks (2). The study reported reductions in disease flare frequency, improvements in other clinical markers, and decreased reliance on glucocorticoids. According to the study data, safety outcomes were consistent with those of previous rilzabrutinib studies, with no new safety signals identified. These results were presented at the 2025 European Alliance of Associations for Rheumatology Congress, held on June 11–13 in Barcelona (1).

Rilzabrutinib is being investigated across multiple rare immune-mediated and inflammatory diseases. In addition to IgG4-RD, the drug has orphan designations for treating immune thrombocytopenia in the United States, European Union (EU), and Japan, as well as for warm autoimmune hemolytic anemia, sickle cell disease, and IgG4-RD in the US (1). In addition, fast track designation has been granted in the US by FDA for both immune thrombocytopenia and IgG4-RD.

Regulatory reviews for rilzabrutinib in immune thrombocytopenia are ongoing in the US, EU, and China. A regulatory decision is expected from FDA by Aug. 29, 2025 (1).

Mechanism and Implications for pharmaceutical development

Rilzabrutinib’s mechanism of action targets BTK, a signaling protein expressed in B cells, macrophages, and other innate immune cells (1). BTK is implicated in multiple immune-mediated disease pathways. Rilzabrutinib’s reversible covalent binding approach, which is enabled by Sanofi’s Tailored Covalency technology, is designed to maintain BTK selectivity while potentially minimizing off-target effects.

The development of rilzabrutinib reflects two broader trends in drug manufacturing and discovery: the application of structure-based drug design to improve target specificity, and the strategic expansion of BTK inhibitors beyond oncology into autoimmune and inflammatory indications. Orphan designation status also provides incentives, such as market exclusivity and regulatory support, which can influence development timelines and commercialization strategies.

IgG4-RD: challenges in diagnosis and treatment

IgG4-RD is a progressive, chronic immune-mediated condition that can affect nearly any organ, causing irreversible organ damage and potentially fatal outcomes (3). The disease course often includes recurrent flares marked by exacerbated symptoms. Although U.S. prevalence is estimated at eight cases per 100,000 adults annually, global epidemiology remains unclear due to diagnostic challenges (3).

Given the limited treatment options and the need to balance efficacy with long-term safety in chronic immune-mediated disorders, pharmaceutical advances in this area carry significance for both patient care and manufacturing innovation. The development of rilzabrutinib demonstrates how targeted immune modulation strategies may open new therapeutic pathways for rare and difficult-to-treat conditions.

Sanofi’s Rilzabrutinib Earns Orphan Designation in the EU for IgG4-Related Disease

. Press Release. Aug. 14, 2025.
2. National Library of Medicine. Open Label Two-Arm Study to Evaluate Rilzabrutinib in IgG4-RDParticipants. 

, last updated Feb. 21, 2025 (accessed Aug. 15, 2025). 

https://clinicaltrials.gov/study/NCT04520451


3. Wallace, Z. S.; Miles, G.; Smolkina, E.; et at. Incidence, Prevalence and Mortality of IgG4-Related Disease in the USA: A Claims-Based Analysis of Commercially Insured Adults. 

 (7), 957–962. DOI: 10.1136/ard-2023-223950



Articles

Sanofi's investigational oral BTK inhibitor, rilzabrutinib, has received orphan designation from the EMA for treating IgG4-related disease, highlighting its potential in rare immune-mediated disorders. This decision follows promising Phase II trial results showing reduced disease flares and improved clinical markers. Rilzabrutinib is also being explored for other conditions like immune thrombocytopenia and warm autoimmune hemolytic anemia. Its mechanism targets BTK, a key protein in immune pathways, and reflects trends in drug design and BTK inhibitor expansion beyond oncology into autoimmune diseases.

Orphan status was granted based on Phase II data showing that treatment with rilzabrutinib reduced flares and improved markers while demonstrating consistent safety.

EMA Grants Orphan Designation to Rilzabrutinib for IgG4-Related Disease

interest and investment in rare disease drug development, interview with SynaptixBio CEO, Dan Williams

The Evolving Landscape of Rare Disease Pharmaceuticals (Part 1)

Rare disease drug development is emerging as a focal point for innovation and investment amid an evolving landscape of pharmaceutical technologies, according to 

® Group. In the interview, Williams highlights the unique challenges and opportunities in targeting such ultra-rare conditions as TUBB4A-related leukodystrophy, a disorder affecting the myelination of nerves in children.

Williams’ experience spans the full spectrum of drug development, from bench science to clinical trials and corporate operations, providing insight into the complexities of bringing novel therapies to market. “About 80% of rare diseases are genetic and have to do with modifications of genes,” he notes, emphasizing the potential for targeted therapies using advanced technologies. For professionals in drug manufacturing and development, the rare disease sector offers scientific challenges as well as significant incentives, including accelerated regulatory pathways and high market value for successful therapies. This shift is drawing increased attention from investors and companies alike, signaling a broader trend toward precision medicine and the rapid advancement of pharmaceutical technology.

Dan Williams, PhD, studied biochemistry and physiology at the University of Dundee, after which he worked his way up to senior scientist—managing a cell research group and preclinical development. Following this, he moved to drug development, focusing on the organization and management of both manufacturing and clinical trials. Williams then moved to Adaptimmune, developing cell therapies. He set up the development groups, project managing preclinical research and clinical trials, before becoming vice-president of Research Operations. From there, he moved to Meatable as chief product officer. Williams co-founded SynaptixBio in 2021.

Videos

Drug development for rare diseases leverages genetic targeting and drives innovation and investment in pharmaceutical technology as well as precision medicine, according to Dan Williams, PhD, CEO, SynaptixBio.

Tokyo-based Nxera Pharma (Nxera) announced on Aug. 6, 2025 the launch of an expanded drug discovery pipeline targeting obesity and related metabolic diseases. The company’s efforts build on independent research in addition to existing collaborations with Pfizer and Eli Lilly and Company, focusing on a range of validated G protein-coupled receptor (GPCR) targets (1–3).

Nxera’s lead asset is a wholly owned oral small molecule glucagon-like peptide-1 (GLP-1) agonist program, which it developed with differentiated chemistry and managed separately from Pfizer’s PF-06954522. Nxera said in a company press release that the separation allows it to maintain full control over development timelines and strategy.

“Nxera scientists were among the pioneers in elucidating the structure of the GLP-1 receptor and other key receptors being targeted, giving us a clear advantage in developing potentially best-in-class next generation drug candidates. For the past 12 months, Nxera scientists have been advancing a broad metabolic disease pipeline to capitalize independently on our differentiated science,” said Chris Cargill, president and CEO, Nxera, in the release (1).

Multiple GPCR-targeted programs in development

In parallel with the GLP-1 program, Nxera is progressing six additional obesity and weight-management drug programs, including:

three small-molecule agonists targeting GIP, apelin, and amylin

one small molecule antagonist targeting GIP

These programs employ Nxera’s NxWave GPCR-focused structure-based design platform with which the company can identify novel lead molecules with distinctive chemistry. The process combines proprietary NxHit small-molecule libraries with NxStaR proteins for DNA-encoded library screening. The company aims to produce candidates that differ from other drugs in global development.

“Today, we reveal the addition of these programs to our discovery portfolio and are confident in achieving significant progress over the mid-term, delivering clear value for shareholders and patients in the rapidly expanding obesity market, projected to exceed US$100 billion annually in global sales [4],” Cargill added in the release.

According to Nxera, its pipeline strategy addresses several industry and clinical priorities such as:

long-term weight maintenance through convenient, scalable oral therapies

treatment of obesity-related co-morbidities, including cardiovascular, renal, and liver diseases

reduced side effects and tailored options for populations such as the elderly, post-menopausal women, and patients with sarcopenia.

Beyond obesity and metabolic disorders, Nxera continues research in neurology, gastroenterology, and immunology, applying the same GPCR-targeted discovery methods.

Pfizer program discontinued, future discussions planned

Separately, Pfizer recently ended development of its Phase I small-molecule GLP-1 agonist PF-06954522 in early August 2025 (5), which originated from a collaboration with Nxera. The decision, according to Nxera, was due to portfolio reprioritization rather than safety concerns. Nxera plans to discuss with Pfizer the possibility of advancing GLP-1 molecules identified during their joint research.

Nxera’s announcements underscore a broader trend in obesity drug development: expanding beyond injectables into oral therapies, diversifying receptor targets, and applying high-throughput, structure-based screening to accelerate discovery. With obesity drug sales forecast to surpass $100 billion annually, the field is poised for increasingly intense scientific and commercial activity.

Nxera Launches Broad Proprietary Pipeline Targeting Obesity and Chronic Weight Management

. Press Release. Aug. 6, 2028.
2. Pfizer. 

Sosei Subsidiary Heptares Enters Strategic Drug Discovery Collaboration with Pfizer Inc. Focused on GPCR Targets Across Multiple Therapeutic Areas

. Press Release. Nov. 30, 2015.
3. Nxera Pharma. 

Sosei Heptares and Lilly Enter Multi-target Collaboration and License Agreement in Diabetes and Metabolic Diseases

. Press Release. Dec. 16, 2022.
4. McKinsey & Co. 

GLP-1s Are Changing Obesity Care. What Comes Next

? mckinsey.com, June 1, 2025 (accessed Aug. 11, 2025).
5. Waldron, J. Pfizer's Embattled Obesity Program Loses Another GLP-1 Over Poor Data and Strong Competition. 

, Aug. 5, 2025 (accessed Aug. 11, 2025). 

https://www.fiercebiotech.com/biotech/pfizers-embattled-obesity-program-loses-another-glp-1-drug

Tokyo-based Nxera Pharma has launched an expanded drug discovery pipeline targeting obesity and related metabolic diseases, leveraging collaborations with Pfizer and Eli Lilly. Their lead asset is a proprietary oral GLP-1 agonist program, developed independently from Pfizer's discontinued PF-06954522. Nxera is advancing multiple GPCR-targeted programs, including small-molecule agonists and antagonists, using their NxWave platform. The pipeline aims to address long-term weight maintenance, obesity-related co-morbidities, and reduced side effects. The company continues research in neurology, gastroenterology, and immunology, applying GPCR-targeted methods.

The new targeted pipeline will advance Nxera’s oral GLP-1 agonists, novel GPCR targets, and structure-based drug design to address obesity and related health conditions.

Nxera’s New GLP-1 and GPCR-Targeted Drug Programs Aim to Advance Obesity and Metabolic Disorder Therapies

Celltrion announced on Aug. 6, 2025 that FDA has approved its application for an expanded indication of tocilizumab-anoh (brand name Avtozma), its intravenous (IV) therapy, to include the treatment of cytokine release syndrome (CRS) in adults and pediatric patients 2 years of age and older (1). Tocilizumab-anoh is a biosimilar to Actemra (tocilizumab), the originator biologic from Genentech, a member of the Roche Group. Actemra was originally approved by FDA in January 2010 (2).

With this additional approval from FDA for the CRS indication, Celltrion’s tocilizumab-anoh IV now aligns with all indications for which Genentech’s originator tocilizumab IV is approved in the United States. Tocilizumab-anoh in IV formulation originally received FDA approval in January 2025 for treating multiple inflammatory indications, including rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and coronavirus COVID-19 (3).

"We are proud that [Avtozma IV] has now achieved full indication alignment with the reference [Actemra IV]. This milestone marks an important step forward in our mission to deliver a safe and effective therapy for CRS," said Thomas Nusbickel, chief commercial officer at Celltrion USA, in a company press release (1). "This FDA approval expands access to high-quality biologics and supports beneficial patient outcomes across multiple therapeutic areas."

CRS is a potentially life-threatening condition. It occurs when the immune system is highly activated, which leads to rapid and excessive release of cytokines into the bloodstream—a cytokine storm. During a cytokine storm, the overactivated immune system can lead to widespread inflammation and can cause damage to healthy tissue and organs throughout the body. Symptoms range from mild, flu-like symptoms to more severe complications, including low blood pressure, difficulty breathing, and multi-organ failure (4).

CRS is a recognized complication of certain T-cell-engaging (TCE) immunotherapies. Such therapies include chimeric antigen T-cell and bispecific therapies. CRS can occur from a severe infection, such as COVID-19. Multiple myeloma drugs that may cause CRS include:

idecabtagene vicleucel (brand name Abecma)

ciltacabtagene autoleucel (brand name Carvykti)

teclistamab-cqyv (brand name Tecvayli) (4).

Settlement between Celltrion and Genentech

In compliance with a patent settlement agreement between Celltrion and Genentech, the IV formulation of tocilizumab-anoh is expected to be available in the US market on Aug. 31, 2025. Celltrion holds a license to market a subcutaneous formulation in the US starting on a licensed launch date, which has not been disclosed.

Tocilizumab-anoh is a recombinant humanized monoclonal antibody that acts as an interleukin 6 receptor antagonist. FDA’s approval was based on data from a global Phase III clinical trial designed to evaluate the efficacy, pharmacokinetics, safety, and immunogenicity of CT-P47 (tocilizumab-anoh’s designation during pipeline development) (3) in comparison to the reference biologic, tocilizumab. The biosimilar also received approval by the European Commission in February 2025.

FDA Approves Expanded Indication for AVTOZMA (tocilizumab-anoh) Intravenous (IV) Formulation in Cytokine Release Syndrome (CRS)

. Press Release. Aug. 7, 2025.
2. FDA. Actemra Approval Letter. 

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125276

US FDA approves Celltrion's AVTOZMA (tocilizumab-anoh), a Biosimilar to ACTEMRA

. Press Release. Jan. 30, 2025.
4. International Myeloma Foundation. 

Celltrion's tocilizumab-anoh (Avtozma) has received FDA approval for an expanded indication to treat cytokine release syndrome (CRS) in patients aged two and older. This approval aligns Avtozma with all indications of Genentech's Actemra, the reference biologic. Tocilizumab-anoh, a biosimilar, was initially approved for various inflammatory conditions. CRS, a severe immune response, can result from T-cell-engaging therapies or infections like COVID-19. A patent settlement allows Celltrion to market the IV formulation in the US from August 31, 2025, with a subcutaneous version pending.

The company’s expanded label for Avtozma (tocilizumab-anoh) now includes the treatment of cytokine release syndrome, aligning the therapy with all indications for which Actemra is approved in the US.

FDA Grants Approval to Celltrion for Expanded Indication of Actemra Biosimilar to Treat CRS

Discussion with Jerry Keybl, Avantor, about latest innovations in biomanufacturing and major industry trends coming out of INTERPHEX 2025.

INTERPHEX 2025: The Search for Pragmatic Solutions to Ground Industry Innovations

Contemporary biopharmaceutical production strategies emphasize three critical drivers: scalability, flexibility, and efficiency, says Jerry Keybl, senior vice-president, Biopharma Products and Strategy, Avantor. In addition, Keybl attended INTERPHEX 2025 last April and shared some of his impressions of the energy at that show around these themes.

Keybl emphasizes how the bioprocessing sector is experiencing significant transformation today, driven by supply chain disruptions, regionalization, and the emergence of diverse therapeutic modalities. He underscores the importance of developing future-proof bioprocessing technologies.

"Innovations today really have to be future-proof. They have to support manufacturing all the way from clinical trials to commercialization. Sometimes the challenges are different at different stages of the development, and the decisions you make early on can really impact the success as a commercialization approaches," he says.

Manufacturing flexibility is increasingly crucial, he also points out, explaining that facilities are transitioning from single-process to multi-product and multi-modality platforms. Therefore, there is a need for adaptable technologies that can accommodate diverse product requirements while maintaining operational efficiency.

Buffer management is also emerging as a crucial area for optimization, with solutions such as ready-to-use buffers and direct dispense packaging systems (solutions that Avantor offers) allowing for the reduction of labor costs and improved process efficiency.

One key takeaway from the show that made an impression on Keybl was that the bio/pharmaceutical industry is currently focused on practical innovation, balancing excitement about new modalities with a pragmatic approach to solving real-world manufacturing challenges.

Click the video above to view the full interview.

Jerry Keybl, Senior Vice-President, Biopharma Products and Strategy, Avantor

Jerry Keybl is senior vice-president of Biopharma Products and Strategy at Avantor, leading integrated product strategy and execution across traditional and novel biopharma modalities. He previously held product management, marketing, and strategy roles at MilliporeSigma, with a focus on cell and gene therapies, and served as a project leader at the Boston Consulting Group.

Jerry Keybl, senior vice-president, Biopharma Products and Strategy, Avantor, discusses innovations in biomanufacturing and recalls his impressions of INTERPHEX 2025 held this past April.

Discussing Pragmatic Solutions to Ground Industry Innovations with Avantor

Eli Lilly and Company (Lilly) announced on July 30, 2025 results from a long-term extension (LTE) of a Phase III study (TRAILBLAZER-ALZ 2), which showed that participants treated with donanemab-azbt (brand name Kisunla) demonstrated slowing of decline (1)—a benefit that continued to grow over a span of three years, compared to an untreated external cohort from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (2). Under the brand name Kisunla, donanemab-azbt was 

 for treating Alzheimer’s disease (AD) (3).

Participants in the Phase III study who began treatment at a later time still saw benefit; however, study participants who started treatment earlier significantly reduced the risk of progression to the next stage of AD compared to those who received treatment later (2). Data from the study were presented at the 2025 Alzheimer's Association International Conference (AAIC) in Toronto, Canada, which occurred on July 27–30.

"The TRAILBLAZER-ALZ 2 long-term extension reaffirms that Kisunla delivered sustained clinical benefit that continued to increase over three years and a consistent safety profile," said Mark Mintun, MD, group vice-president, Neuroscience Research & Development, Eli Lilly and Company, in a company press release (1). "Participants continued to show meaningful outcomes, reinforcing the long-term value of early intervention."

This Phase III LTE study (TRAILBLAZER-ALZ 2 LTE) was a double-blind extension of the original Phase III clinical trial (TRAILBLAZER-ALZ 2) designed to evaluate the efficacy and safety of donanemab-azbt in individuals with early symptomatic AD (2). Participants originally treated with donanemab-azbt were either continued on the same treatment or were switched to placebo, while those initially on placebo began treatment with donanemab-azbt in a blinded manner. To assess outcomes against a matched, untreated population, an external comparator group from ADNI was used.

The key preliminary results from the LTE study include:

The demonstration that the donanemab-azbt benefit continued to grow over the course of three years in study participants treated with the therapy compared to those in the matched ADNI group. The data show that donanemab-azbt reduced cognitive decline by -0.6 at 18 months and -1.2 at 36 months based on the Clinical Dementia Rating Sum of Boxes (CDR-SB). These data came from patients initially treated with the therapy in the core study compared to the ADNI group.

An earlier start of treatment with donanemab-azbt reduced the risk of disease progression to the next stage by 27% on the Clinical Dementia Rating-Global Score (CDR-G) compared to the group who had delayed initiation of treatment.

More than 75% of participants treated with donanemab-azbt achieved amyloid clearance within 76 weeks from the start of treatment.

Observed data gathered after up to 2.5 years in participants who had completed treatment showed that the reaccumulation of amyloid plaque remained slow at a rate of approximately 2.4 CL/year, which was consistent with prior observations and modeling.

No new safety signals were observed in the study over the three-year period, which supports the established safety profile for donanemab-azbt.

Side effects include amyloid-related imaging abnormalities (ARIA) with edema/effusion (ARIA-E) and with hemorrhage/with hemosiderin deposition. These are side effects within the class of amyloid targeting therapies that do not usually cause any symptoms; however, serious and life-threatening symptoms can occur. ARIA can be fatal, according to Lilly in the release.

Lilly’s Kisunla (donanemab-azbt) Showed Growing Benefit Over Three Years in Early Symptomatic Alzheimer’s Disease

. Press Release. July 30, 2025.
2. National Library of Medicine. 

A Study of Donanemab (LY3002813) in Participants with Early Alzheimer's Disease (TRAILBLAZER-ALZ 2)

, May 4, 2025 (accessed Aug. 5, 2025).
3. FDA. 

Eli Lilly's long-term extension of the Phase III TRAILBLAZER-ALZ 2 study demonstrated that donanemab-azbt (Kisunla) significantly slowed cognitive decline in Alzheimer's patients over three years. Early treatment initiation notably reduced disease progression risk compared to delayed treatment. The study, presented at the 2025 Alzheimer's Association International Conference, confirmed sustained clinical benefits and a consistent safety profile. More than 75% of participants achieved amyloid clearance within 76 weeks, with slow amyloid plaque reaccumulation. No new safety concerns were identified, although amyloid-related imaging abnormalities remain a potential risk.

Findings from a Phase III study highlight the demonstrated action of donanemab-azbt (brand name Kisunla) in slowing the decline of patients exhibiting early symptomatic Alzheimer’s disease. 