Pemphigus: A New Era in Treatment with Biologics

Pemphigus is a rare autoimmune blistering disorder affecting the skin and mucous membranes. This disease is characterized by the presence of antibodies against desmogleins, proteins that help maintain the structure of the skin. When these antibodies are produced, they lead to the breakdown of the bonds between skin cells, causing blisters and sores. Untreated, pemphigus can be life-threatening due to severe skin damage, infection, and fluid loss.

Historical Treatment Landscape

Historically, pemphigus was a fatal disease, with a mortality rate reaching as high as 90% before the introduction of systemic corticosteroids. With corticosteroid therapy, mortality dropped significantly. However, long-term use of corticosteroids has been associated with serious side effects, such as osteoporosis, diabetes, and an increased risk of infection. Thus, the need for safer and more effective treatments drove the exploration of immunosuppressive therapies, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, which were used alongside corticosteroids.

Rituximab: A Game-Changer in Pemphigus Treatment

The development of Rituximab, a monoclonal antibody targeting CD20-positive B cells, revolutionized the treatment of pemphigus. Rituximab became the first biologic approved by the U.S. FDA for treating moderate to severe pemphigus vulgaris (PV) in 2018. The approval was based on the successful Ritux 3 trial, which demonstrated a significant increase in remission rates when Rituximab was used alongside short-term corticosteroids compared to corticosteroids alone.

Key Milestones:

• First FDA-approved biologic for pemphigus vulgaris.
• Achieved orphan drug status and received priority review and breakthrough therapy designation.

Emerging Treatments and Ongoing Clinical Trials

The success of Rituximab opened the door to a range of new treatments, focusing on B-cell targeting therapies and other innovative mechanisms to control autoimmune responses. Several companies and treatments are in various stages of development, some of which have received FDA Orphan Drug Designation (ODD) for pemphigus:

Recent FDA Orphan Drug Designations:

• Cholgene Therapeutics: Received ODD for its novel compound targeting autoimmune conditions.
• Shanghai Yidian Pharmaceutical Technology: Working on advanced biologics for pemphigus treatment.
• Principia Biopharma: Developing Bruton’s tyrosine kinase inhibitors (BTKi) for autoimmune disorders, including pemphigus.

Additionally, ongoing clinical trials are exploring new therapies like:

1. Bruton Tyrosine Kinase Inhibitors: Acalabrutinib and zanubrutinib are under investigation for treating pemphigus.
2. Chimeric Autoantibody Receptor (CAR) T-Cells: Preclinical studies are exploring how modified T-cells can selectively target B-cells that produce harmful antibodies.
3. T-Cell Focused Approaches: There is ongoing research into therapies aimed at restoring immune tolerance in T-cells that are reactive to desmoglein proteins.

Companies Leading the Pemphigus Treatment Landscape

• Roche/Genentech: Developing Rituximab and working on additional autoimmune disease therapies.
• Argenx: Researching efgartigimod, a promising therapy for various autoimmune diseases, including pemphigus.
• Sanofi: With the acquisition of Principia Biopharma, Sanofi is focused on advancing BTKi treatments for autoimmune disorders like pemphigus.

Mergers and Acquisitions in the Pemphigus Space

Over the last few years, the pemphigus treatment landscape has witnessed a significant surge in mergers and acquisitions (M&A), reflecting a growing interest from major pharmaceutical companies in autoimmune diseases. Some of the most notable M&A activities include:

1. Sanofi’s Acquisition of Principia Biopharma (2020):?In a deal valued at $3.7 billion, Sanofi acquired Principia Biopharma, a company specializing in Bruton’s Tyrosine Kinase (BTK) inhibitors. This acquisition was a strategic move to expand Sanofi’s presence in autoimmune diseases, including pemphigus. Principia’s rilzabrutinib, a BTK inhibitor, has shown potential in treating pemphigus by targeting B-cell pathways, reducing autoimmune activity without affecting normal immune functions.
2. Roche’s Collaboration with Immunocore:?Roche?has entered into a collaboration with Immunocore, a company known for its work on immune-modulating therapies. This partnership aims to develop immune-mediated therapies, which include potential treatments for autoimmune disorders like pemphigus.
3. Roche’s Acquisition of Spark Therapeutics:?While primarily focused on gene therapies, Roche’s acquisition of Spark Therapeutics has broadened its portfolio in autoimmune diseases, with potential spillover benefits for pemphigus treatment research.

Venture Capital Investments in Pemphigus Therapies

The surge in biotech innovations for autoimmune diseases, including pemphigus, has attracted the attention of several prominent venture capital (VC) firms. These firms have been instrumental in funding early-stage biotech companies focused on developing new therapies for pemphigus.

1. Third Rock Ventures:?A leading venture capital firm, Third Rock Ventures?has made significant investments in biotech startups working on autoimmune therapies. Their portfolio includes companies developing novel therapies targeting the immune system, some of which are exploring treatment options for pemphigus.
2. Arch Venture Partners:?Arch Venture Partners?has a strong track record of backing companies that develop cutting-edge therapies for immune-mediated diseases. By investing in early-stage companies, Arch has played a crucial role in advancing research on pemphigus and other autoimmune disorders.
3. Venrock: Venrock?has invested in companies working on next-generation biologics, including therapies targeting autoimmune diseases like pemphigus. Their investment strategies have supported the development of innovative therapies aimed at modulating the immune response in autoimmune disorders.

Future Outlook: A Shift Towards Targeted Therapies

The future of pemphigus treatment looks promising, with a shift toward targeted therapies and precision medicine. The success of biologics like Rituximab has paved the way for the development of more advanced treatments. B-cell-targeting therapies, next-generation BTK inhibitors, and emerging immunotherapies are expected to improve outcomes and reduce the reliance on corticosteroids. Furthermore, advancements in biotechnology, combined with a deeper understanding of the disease's molecular mechanisms, are likely to lead to more personalized treatment approaches in the coming years.

In conclusion, the evolution of pemphigus treatment, from high-dose corticosteroids to targeted biologics, marks a significant milestone in the management of this once fatal disease. With ongoing research and investment, the outlook for pemphigus patients continues to improve, offering hope for more effective management or even a cure in the near future.

The writer of this article is Nana Mainoo, PharmD, MA, Principal Consultant and CEO at Cleracs Consulting. With over 16 years of experience in the healthcare industry, Nana specializes in regulatory strategy, M&A, licensing, and fundraising, helping biotech companies navigate complex regulatory landscapes and accelerate their growth.