Rapid, Transient Engraftment with Long-term Benefits

Dilanubicel (NLA101) is a universal donor, off-the-shelf, ex vivo expanded hematopoietic stem and progenitor cell product that provides rapid, transient hematopoiesis with long-term benefits. Dilanubicel was intentionally developed to be a short-term therapy that provides temporary bone marrow function that persists 2-3 weeks until a patient’s immune system recovers while inducing long-term immunologic benefits with the potential for improved survival.

Dilanubicel is efficiently manufactured ahead of time, cryopreserved, and available for immediate use. NLA101 is differentiated from other autologous or patient-specific allogeneic cell therapies as it does not require tissue matching. It is currently the subject of two Phase 2 clinical trials to improve treatment outcomes in patients receiving cord blood transplants, and for patients receiving high-dose chemotherapy.

Dilanubicel for Cord Blood Transplants

Widespread adoption of cord blood transplants is currently limited by the low cell dose provided in a cord blood graft. On average, a cord blood graft contains one tenth the number of stem and progenitor cells compared to other stem cell sources, specifically hematopoietic stem cell grafts from bone marrow or peripheral blood donors. As a result, patients receiving a cord blood transplant are at increased risk for significantly-delayed engraftment or graft failure and experience higher early transplant-related morbidity and mortality compared with patients receiving bone marrow or peripheral blood stem cell transplants.

Dilanubicel has the potential to address this limitation by instantly providing significantly-increased numbers of stem and progenitor cells capable of rapid production of blood and immune cells. Clinical results to date demonstrate that dilanubicel may reduce morbidity and mortality associated with cord blood transplants and improve overall patient survival. In June 2018, the European Medicines Agency (EMA) granted dilanubicel PRIority MEdicines (PRIME) designation for the treatment of patients receiving an HSCT. Since its inception in 2016, only 21% of PRIME requests have been granted by the EMA. Nohla was also granted Orphan Drug designation for dilanubicel in HSCT by the European Commission in January 2018.

Dilanubicel following Intensive Chemotherapy

Dilanubicel is also in clinical development for patients receiving intensive chemotherapy. In these patients, life-threatening infections are very common, leading to lengthy hospitalization and increased reliance on supportive care.  Despite the use of growth factors and antibiotics, nearly 40% of patients treated with high-dose chemotherapy still experience infections, which can be life threatening. In addition, patients who experience serious infections are often required to delay the start of additional chemotherapy cycles or have their chemotherapy dose reduced to avoid ongoing complications. These delays or reductions in treatment may lessen chemotherapy’s effectiveness and its ability to induce long-term disease response.

Dilanubicel provides these patients with additional treatment options by reducing toxicities associated with intensive chemotherapy, allowing for earlier administration of chemotherapy which could lead to improved patient outcomes.

Dilanubicel: Ongoing Clinical Trials

Nohla has advanced dilanubicel into two large randomized, multi-center Phase 2 studies. The first is an ongoing Phase 2b study in the US for patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, myelodysplastic syndromes or chronic myelogenous leukemia undergoing a myeloablative cord blood transplant. Enrollment is now complete (160 patients). The goal of the trial is to determine whether adding dilanubicel to standard donor cord blood transplant decreases the time to hematopoietic recovery, thereby reducing associated morbidities and mortality. More information can be found at clinicaltrials.gov.

The second Phase 2 global trial, called LAUNCH (NCT03301597), will enroll approximately 220 adult patients and will evaluate dilanubicel’s ability to reduce the rate of ≥ Grade 3 infections associated with chemotherapy-induced neutropenia, and identify the lowest effective cell dose of dilanubicel. Patients in the Phase 2 study are being randomized to one of three investigational treatment arms or a control arm. Patients randomized to an investigational treatment arm are eligible to receive a single fixed dose of dilanubicel after the first cycle of chemotherapy, and up to two additional identical dilanubicel doses after subsequent cycles of chemotherapy. Additional information on this trial can be found at https://clinicaltrials.gov/show/NCT03301597. Funding for the LAUNCH trial is supported by a $6.92 million grant from the California Institute for Regenerative Medicine.

Dilanubicel: Clinical Results

Over 125 infusions of dilanubicel have been administered across four clinical trials since 2009 with no unexpected safety issues to date. Between 2010 and 2012, 15 patients with hematologic malignancies were enrolled in a single center, Phase 2 trial to assess safety and feasibility of infusing dilanubicel to augment myeloablative cord blood transplant. In June 2018, data from this study demonstrating rapid immune recovery and improved long-term outcomes in Hematopoietic Stem Cell Transplant (HSCT) patients were presented at the 23rd Congress of European Hematology Association (EHA) Annual Conference in Stockholm.

In addition, a Phase 1 trial evaluating the safety and preliminary efficacy of infusing dilanubicel following intensive chemotherapy was conducted in 29 adult patients with AML. Dilanubicel was administered after chemotherapy with clofarabine, cytarabine and G-CSF priming. A total of 42 infusions were administered to the 29 patients, with 13 patients going on to receive a second cycle of chemotherapy with dilanubicel. No unexpected toxicities, transfusion-associated GVHD, or dilanubicel-induced alloimmunization were observed. As compared with concurrent controls the rates of documented infections were significantly reduced, and no gram-negative rod bacteremia (for example, E. coli, which can rapidly progress in this setting from severe GI infection to sepsis) was observed in patients who received dilanubicel (Delaney et al, Lancet Haematology 2016).