In healthy individuals, the immune system produces cells that are potentially capable of attacking “self,” but such cells are either eliminated or silenced by regulatory mechanisms within the body.
However, if these mechanisms fail, or if an infection introduces a foreign antigen that mimics a self-antigen, the immune system can mount an attack on an individual’s own cells, tissues, or organs, either locally or systemically. This phenomenon is termed autoimmune disease, and reflects the absence of immune tolerance to some aspect of self. There are more than 80 recognized types of autoimmune diseases.
Facilitated Allo-HSCT Therapy has the potential to restore self-tolerance in patients suffering from severe autoimmune diseases by eradicating diseased autoreactive cells and regenerating a new and healthy supply of immune cells, thereby halting the autoreactive cells’ attack on one’s own body.
Allogeneic HSCT for Severe Autoimmune Disease
HSCT is not an approved treatment for autoimmune disorders, but it has been shown in clinical trials and practice to have curative potential for certain severe autoimmune diseases—notably scleroderma, multiple sclerosis and Crohn’s disease.
To date, autologous HSCT has been preferred to allogeneic HSCT in these trials because the latter carries a significant risk of graft versus host disease (GvHD) as well as a greater risk that the donated stem cells will fail to engraft in the recipient. GvHD occurs when immune cells that are produced by donor-derived stem cells that have engrafted in the recipient attack the recipient’s body as “non-self.” GvHD, which can be acute (within the first 100 days following transplant) or chronic (beyond 100 days), can cause potentially life-threatening damage to the liver, skin, mucosal tissues, and gastrointestinal tract.
In autologous HSCT, a patient’s own HSCs are first procured and then the patient’s entire immune system, including the autoreactive cells, is eliminated by myeloablative conditioning. The previously procured stem cells are then transplanted back into the patient, where they engraft and then differentiate into mature immune cells. The underlying principle is that these newly created immune cells have the potential to reset the patient’s immune system, and enable disease remission.
Autologous HSCT has two major limitations. First, the acute toxicity of myeloablative conditioning, notably to the heart, lungs, and kidneys, necessitates a long and costly hospitalization and restricts its use solely to the patients who can tolerate its intensity. Moreover, there are important long-term complications of myeloablative conditioning, including significantly increased risk of infections and hematological malignancies. Second, since these patients likely have a genetic predisposition towards autoimmune diseases, there is a higher risk of recurrence, which should be lower if stem cells were transplanted from a healthy allogeneic donor.
About scleroderma (SSc)
Scleroderma is a rare, clinically heterogenous, progressive, multisystem, chronic autoimmune disorder that primarily affects the connective tissues. Scleroderma can be localized or systemic, with the latter manifestation termed systemic sclerosis (SSc). SSc has a prevalence of approximately 70,000 to 80,000 individuals in the United States, about 80% of whom are women aged 30 to 50. SSc is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy, and the presence of autoantibodies against various cellular antigens.
The etiology of this disorder is largely unknown, but research suggests it is due to both genetic and environmental factors that lead to dysregulation of the innate and adaptive immune systems, dysfunctional inflammatory responses, and connective tissue repair injury in susceptible individuals. The most severe form of SSc, diffuse cutaneous SSc (dcSSc), has a poor prognosis and may progress rapidly, affecting areas throughout the body. We estimate that approximately 40% of systemic sclerosis patients are diagnosed with the most severe form of SSc, diffuse cutaneous SSc (dcSSc).
Potential for Facilitated Allo-HSCT Therapy in Severe Scleroderma
Recently, autologous HSCT has emerged as a promising and potentially disease-modifying treatment for patients with dcSSc at risk for organ failure. Data to date indicate that autologous HSCT for this indication may require a myeloablative regimen to be most effective; higher rates of relapse have been observed when less intensive conditioning regimens have been used. Nevertheless, disease recurrence still was observed in autologous HSCT patients, presumably in part because the patient’s own diseased stem cells are being reinfused in the patient.
Allogeneic HSCT offers a promising alternative therapy to autologous HSCT for patients diagnosed with dcSSc. The advantage of allogeneic HSCT is its ability to replace the immune system with cells from healthy donors that lack the genetic predisposition for a return to autoimmunity, and with the potential of inducing tolerance to both auto-antigens and allo-antigens. We believe that our Facilitated Allo-HSCT Therapy, which combines administration of FCR001 with a nonmyeloablative conditioning regimen, could additionally offer a less toxic alternative to autologous HSCT (which generally requires a fully myeloablative conditioning regimen), and has the potential to enable broader use of allogeneic HSCT with a lower risk of GvHD than current approaches.
Notably, in our Phase 2 LDKT trial, all seven LDKT recipients who required a kidney transplant as a result of a kidney-related autoimmune disease, and could be withdrawn from chronic immunosuppression at one year following FCR001 treatment, have not experienced recurrence of their prior kidney-related autoimmune disease. We believe that this observation, as well as the current use of HSCT for severe scleroderma and unmet needs with current approaches therein, supports advancing FCR001 into clinical trials for this indication.
FREEDOM-3 Trial of FCR001 in Severe Scleroderma
We have initiated a Phase 2 trial of FCR001 in scleroderma, called FREEDOM-3. Learn more >>