Adenosine deaminase deficiency

Pictured: diverse group over colorful abstract background/Taylor Tieden for BioSpace Rare diseases currently afflict 300 million people worldwide and 30 million people in the U.S. alone. However, 95% of these diseases lacked an FDA-approved treatment as of January 2023. One reason, industry leaders say, is cost. A 2019 study estimated that orphan drug trials cost researchers $166 million per approved drug. Prices for drugs that hit the market in 2023 were 35% higher than those commercialized in 2022, a change that a Reuters analysis attributed to rare disease therapies that aren’t “big sellers” because of their limited target population. Pharmaceutical companies maintain that restricting drug prices will harm innovation, especially for rare diseases, but health economists argue it is possible to both lower prices and foster innovation by investing in companies and research. On Rare Disease Day, BioSpace looks at some of these investments, as well as the status of the treatment pipeline and what is required to bring more treatments to the market. Industry and Government Investment There has been considerable recent investment in rare disease treatments—from small molecule drugs to antibodies and cell and gene therapies. In July 2023, Biogen acquired Reata Pharmaceuticals and its small molecule Friedreich’s ataxia drug Skyclarys for $7.3 billion. And according to the Alliance for Regenerative Medicine (ARM), around $11.7 billion was invested in cell and gene therapies worldwide in 2023, and five gene therapies were approved for rare disorders last year. Other industry players include Chiesi Ventures, which specifically invests in companies focused on rare diseases, and Deerfield Management, which in 2023, partnered with Invitae to develop genetic treatments for rare diseases. Many early-stage investments in research and development come from the U.S. government. The Orphan Drug Act, passed by Congress in 1983, incentivizes companies to develop treatments for rare diseases using tax credits and grants. State governments can play an important role as well. The California Institute for Regenerative Medicine (CIRM) funds research, clinical trials and drug development for a variety of rare conditions such as ADA-SCID, a very rare condition where patients lack virtually all immune protection from infectious bacteria, viruses and fungi. CIRM is a member of the Bespoke Gene Therapy Consortium (BGTC), a public-private partnership including the NIH, FDA, patient advocacy groups (PAG), venture funds and pharmaceutical companies. The consortium aims to streamline the regulatory process for adeno-associated virus (AAV) vector–based therapies and has acquired $97 million in commitments since it launched in 2021. CIRM’s involvement has allowed the BGTC to address more rare diseases than it had originally planned, said P.J. Brooks, consortium co-chair and deputy director of the Division of Rare Diseases Research Innovation at the NIH’s National Center for Advancing Translational Sciences. “[CIRM has] really stepped up and we’ve been able to develop a partnership with them that I think is quite novel because they are also a major funder of research,” Brooks told BioSpace. Earlier this month, CIRM granted $4 million to Elpida Therapeutics, another BGTC member, to develop an AAV therapy for Charcot-Marie-Tooth disease type 4J, a rare, progressive neurologic disorder involving muscle weakness. CMT4J is one of eight rare diseases the consortium is prioritizing for clinical trials. Elpida is “optimistic” it will be able to launch a clinical trial within the next year, CEO Terry Pirovolakis told BioSpace in an email. The company has registered a clinical trial to study the natural history of CMT4J. Patient Groups Drive R&D, Investment Patient advocate groups (PAG) also play a key role in supporting research for rare diseases. In addition to being experts on their conditions, they may also raise funds for studies and trials. In addition to reviewing research proposals and helping partners find patients for clinical trials, the National Organization for Rare Diseases (NORD) and its member organizations help raise funds for researchers, Pamela Gavin, the organization’s chief operating officer, recently told BioSpace. PAGs helped bring the first targeted therapies for progeria and Friedreich’s ataxia to the market. Pirovolakis founded Elpida after his son was diagnosed with spastic paraplegia 50, a progressive neurological disorder that is also part of the BGTC portfolio. The company’s SPG50 drug Melpida is currently in clinical trials. “Since treating my son, between CureSPG50 and Elpida Therapeutics, we've been able to treat three more children,” Pirovolakis noted. It is “undeniably a challenging period” for rare disease drug developers, he added, especially for those targeting conditions that affect children. Although biotech investment in rare diseases increased between 2020 and 2021, investment decreased overall in 2022. Additionally, while children make up half of rare disease patients in the U.S., only a third of orphan drug indications approved between 2010 and 2018 targeted pediatric patients. Brooks estimated that in the future, “entities that are different from what we think of as pharmaceutical companies” will be more involved in the commercialization of these drugs. He said novel business models that take advantage of the “platform capacity” of gene editing and gene therapy, for example, could be what ultimately brings forward drugs for “very, very rare diseases.” A Healthy Pipeline Several biopharma companies are on the case. In 2021, the Rare Disease Company Coalition launched to advocate for policies that will help bring more treatments to market. There are more than 700 rare disease treatments in the pipeline, according to the Pharmaceutical Research and Manufacturers of America (PhRMA). Large companies such as Takeda, Sanofi and Genethon are among the leaders, with each company possessing at least 10 investigational drugs. And there were 1,329 ongoing cell and gene therapy trials involving rare diseases as of December 2023, according to data collected by ARM, with about 44% of those trials in Phase I. The same data indicate that later-stage trials are less likely to be sponsored by non-industry entities. Brooks noted that one of the challenges in making rare disease treatments more accessible is actually getting them to market. “There’s a big difference between [research] and then actually filing the license that will allow you to sell the drug,” he said. “There’s a whole . . . step in the regulatory process there that is a much bigger step than I was aware of, and taking that next step takes a lot of money.” Pirovolakis noted that while there has been an increase in families pursuing treatments, there has been a decrease in companies focusing on these diseases and a greater number of programs being discontinued. “Currently, rare diseases affecting pediatric patients are severely underfunded, including in the realm of biotech investment,” he said. “To drive progress in treating these diseases, essential support from governments, philanthropists and the biotech investment community is urgently needed.” Nadia Bey is a freelance reporter in North Carolina. Her work and contact information can be found at nadiabey.com.

SAN DIEGO, CA, USA I January 17, 2024 I Tr1X, Inc. today announced its emergence from stealth with a $75 million Series A financing to bring universal allogeneic regulatory T (Treg) and CAR-Treg cell therapies to the clinic to treat and potentially cure autoimmune and inflammatory diseases. The financing was led by Bay Area-based The Column Group, with participation from NEVA SGR and Alexandria Ventures. The Company appointed William Lis Chief Executive Officer, strengthened its leadership team with other biopharma industry veterans, and announced members of the Board of Directors and Scientific Advisory Board. "We are thrilled to partner with Bill Lis, Maria Grazia Roncarolo and Tr1X's world-class team to revolutionize the field through its innovative, breakthrough science," said Leon Chen, Ph.D., MBA, Partner at The Column Group and Tr1X Board Member. "With its experienced management team at the helm, we are confident in Tr1X's ability to bring curative cell therapies to patients who currently require life-long treatment and management." Science and Pipeline The Company's science is primarily based on the work of Tr1X's Scientific Founder Maria Grazia Roncarolo, M.D., the discoverer of Type 1 regulatory T (Tr1) cells, which have features that can benefit patients with autoimmune and inflammatory diseases. Tr1 cells, a differentiated subpopulation of regulatory T cells, are crucial for maintaining homeostasis and tolerance in healthy individuals and have several important functions. These include dampening of local inflammation and downregulation of the inflammasome, suppression of pathogenic effector T cell responses, and induction of long-term tolerance as observed in preclinical models and patients. Tr1X's proprietary technology enables the conversion of CD4 + T cells isolated from healthy donors into Treg-like cells that have a similar function and profile to naturally occurring Tr1 cells. These cells can be further engineered to target specific tissues or organs to enable local, targeted immunomodulation. With a proprietary, GMP-grade, closed-loop system that provides consistency, quality and reliability at scale, Tr1X can enable production of its products at commercial volume. Currently, Tr1X is working on its first investigational Tr1 cell therapy, TRX103, which it plans to evaluate in a Phase 1 trial to prevent Graft versus Host Disease (GvHD) in patients undergoing mismatched hematopoietic stem cell transplant. The Company is developing additional pipeline programs to treat inflammatory bowel disease, Type 1 diabetes and multiple B-cell mediated autoimmune diseases. "The ability to develop a pipeline of medicines based on our work on regulatory T cells represents the culmination of decades of discovery and research into the underpinnings of immunological tolerance and autoimmunity," said Dr. Roncarolo, Scientific Founder, President and Head of R&D at Tr1X. "Tr1 cells have unique properties and represent the ideal therapeutic platform from which to develop 'immune reset' products. Our two platforms have the required attributes to address a broad set of indications, including dual targeting of pathogenic T and B cells. These engineered cells have the potential to induce tolerance, which could transform the lives of people living with chronic autoimmune diseases by providing them with a cure instead of ongoing treatment." Proven Leadership Team, Board of Directors and Scientific Advisory Board Tr1X is led by industry veterans with cell therapy expertise who have a track record of discovery, development and commercialization of more than a dozen novel first- or best-in-class medicines. Chief Executive Officer William "Bill" Lis has more than 25 years of biotech executive leadership experience in building companies and product pipelines from R&D stage through commercialization. He most recently served as Chairman and interim CEO of Jasper Therapeutics, Inc., from 2019 to 2022, where he led the company's Series A and follow-on financings and successful brequilimab Phase 1 study readouts in hematopoietic stem cell transplantation. Before that, he served as Chief Executive Officer and a Director of Portola Pharmaceuticals, Inc. from 2008 to 2018 after serving as Chief Operating Officer, where he built the company from a private research-stage startup into a multi-billion dollar public company that launched Andexxa ® and Bevyxxa ® . Portola was acquired by Alexion Pharmaceuticals, Inc. in 2020. Previously, Mr. Lis held executive positions at Scios, Inc. (a Johnson & Johnson company) where he last served as Senior Vice President of New Product Development and Business Development, leading in-licensing efforts, development and commercial P&L operations for Xarelto ® and the company's therapeutics pipeline. Earlier in his career, he held positions at Millennium Pharmaceuticals, Inc., COR Therapeutics, Inc. and Rhone Poulenc Rorer. He is a director of Zai Laboratories, Inc. Scientific Founder, President and Head of R&D Dr. Maria Grazia Roncarolo is the George D. Smith Professor in Stem Cell and Regenerative Medicine, Professor of Pediatrics and Medicine, Founder of the Center for Definitive and Curative Medicine, and former Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. Dr. Roncarolo has spent her career translating discoveries in immune-mediated diseases and regenerative medicine into novel patient therapies. She and her team were the first to discover Type 1 regulatory T cells in patients and the first to develop curative treatments for ADA-SCID. A pediatric immunologist by training, she was instrumental in bringing novel cell and gene therapies to market, including Strimvelis ® and Libmeldy ® . She is a Co-Founder of the gene-editing companies Graphite Bio and Kamau Therapeutics. Co-Founder and Chief Operating Officer David de Vries has over a decade of experience founding and scaling companies at the intersection of healthcare, biology and technology. Prior to Tr1X, he was Co-Founder and Chief Operating Officer of Arine, a medication intelligence and therapeutic optimization company he helped start, launch and scale to serve millions of patients, working with some of the largest healthcare organizations in the U.S. Previously, he worked at Proteus Digital Health, an innovative drug-device company and the first in the field to obtain FDA approval for a digital medicine, Abilify MyCite ® . "Tr1X is committed to bringing cures to millions of patients suffering from autoimmune diseases through our scalable, universal allogeneic cell therapy process that has been demonstrated to yield billions of cells in a single run," said Mr. Lis, CEO of Tr1X. "In just 18 months, the Tr1X team has successfully closed a Series A financing and extension, assembled an experienced leadership team, board of directors and scientific advisory board, and established a scalable GMP-grade manufacturing process. We are well positioned to advance our pipeline of first-of-their kind allogeneic engineered Treg and CAR-Treg cell therapies that have the potential to address the significant limitations of current cell therapies for autoimmune diseases, which include, among others, poor trafficking, lack of stability, limited persistence and induction of cytokine-associated toxicities, at a fraction of the cost per dose." In addition to Mr. Lis, Dr. Roncarolo and Mr. de Vries, the Tr1X leadership team includes Xavier Paliard, Pharm.D., Ph.D., Chief Scientific Officer; James Adams, MBA, Chief Technical Officer; Jonathan Perrin, J.D., Co-Founder and General Counsel; and Erik Poulsen, M.S., Head of Regulatory Affairs. Joining Mr. Lis and Dr. Roncarolo on Tr1X's Board of Directors are: Tr1X has recruited experts in immunology, stem cell and gene therapy, T-cell biology and immune-mediated diseases to join its Scientific Advisory Board. They include: About Tr1X Tr1X is a privately held biotechnology company focused on engineering cures for immune and inflammatory diseases. Founded by industry veterans, including the scientists behind the discovery of Tr1 cells, the company's pipeline of universal allogeneic cell therapies is being developed for diseases with high unmet medical need. The company is headquartered in San Diego, has developed a robust intellectual property portfolio, and is backed by leading investors, including The Column Group, NEVA SGR and Alexandria Ventures. For more information visit: www.tr1x.bio . SOURCE: Tr1X

Before her arrival, Stefanski was an associate professor of pediatrics at the University of Minnesota and was actively involved in clinical care and research involving children with life-threatening blood and immune system disorders. One of her areas of focus was the use of cord blood units in stem cell transplants and other cellular therapy. She is board certified in both Pediatrics and Pediatric Hematology-Oncology. In the last two decades, there has been a rapid evolution in the diagnosis and treatment of primary immunodeficiencies and the recognition of immune dysregulation, could you explain a) why this is and b) what point we are at currently with the diagnosis and treatment? ​ We are more sophisticated with our molecular techniques of detecting genes in these disorders.  There are approximately 500 inborn errors of immunity causing genes and with the widely available sequencing methods this number continues to grow rapidly. Established treatment options currently consist of immune modulatory drugs, antimicrobial prophylaxis, immunoglobulin replacement therapy and, allogeneic hematopoietic stem cell transplantation (HSCT) as well as gene therapy. Could you explain what causes inborn errors of immunity? ​ Inborn errors of immunity (IEI) are caused by genetic mutations. They can be x-linked, autosomal dominant or autosomal recessive.  They can also be novel mutations that are not inherited. IEI present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Until recently, management of treatment options were limited to prompt treatment of infections, gammaglobulin replacement and even bone marrow transplant depending on what was wrong. Could you outline the newer therapies including small molecule inhibitors, biologics, gene therapy etc? ​ In all types of gene therapy for IEI, ex vivo ​ gene therapy is used, in which a viral vector  is used to genetically modify cells from the patients with therapeutic intent. Gene editing can also be used where the DNA is repaired. Gene therapy has been used for multiple IEI including X-linked SCID, Artemis SCID, X-SCID, Wiskott-Aldrich Syndrome and Chronic Granulomatous Disease. What difference have these made to the patients? ​ These patients live longer, healthier lives and have a much better quality of life.  They are not hospitalized as frequently, they can attend school, they no longer need transfusions.  These therapies are life changing. What efforts have been made to increase awareness of IEI? ​ The advancement of genetic testing and diagnostic techniques have increased the awareness of IEI.  There are educational efforts to recruit young immunologists to the field as well as encouraging international collaborations. The development and widespread use of newborn screening have helped to identify severe combined immune deficiency (SCID) has also increased awareness.  These patients are identified immediately and have improved outcomes.  There are continual improvements and accessibility of genetic sequencing has accelerated identification of new IEI diseases. Advances and improvements in both gene therapy and hematopoietic stem cell transplant have made treatments possible in otherwise fatal diseases. Could you explain ‘newborn screening’ and the advantages or any disadvantages this may have? ​ Newborn screening identifies conditions that can affect a child’s long-term health or survival and is done within 24 hours after birth. Early detection, diagnosis, and intervention can prevent death or disability and enable children to reach their full potential.  The advantages are detecting life-threatening disorders early will impact that child’s health. Each year, new disorders, including IEI, can be detected on newborn screen.  The number of disorders detected varies by state. Where would you like to see this field in terms of development within the next decade or two? ​ A number of gene therapy trials using viral gene addition have been successful for ADA-SCID. Importantly, gene therapy approaches have become safer, more efficient and applicable to more IEI. Techniques for gene therapy continue to evolve and challenges include targeting the specific gene and minimizing the off-targets mutagenesis. The biggest obstacles remain cost and complex regulatory pieces. Where is the industry at with inborn errors of immunity? ​ We are continuing to improve gene therapy and expanding it to other IEIs.  We are making hematopoietic stem cell transplant safer for those that require transplant. The treatment for these disorders will change significantly in the next 10-20 years with more patients receiving gene therapy and additional IEIs being treated with gene therapy. We are truly on the cusp of novel therapies for these patients.