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REHOVOT, Israel—Kamada Ltd., a plasma-derived protein therapeutics company focused on orphan indications, recently reported the interim results from its Phase 2 trial of intravenous Alpha-1 Antitrypsin (IV-AAT) for the prevention of lung transplant rejection following one year of treatment for all patients. AAT is a protein derived from human plasma with known and newly discovered therapeutic roles given its immunomodulatory, anti-inflammatory, tissue-protective and antimicrobial properties.
The results, announced Feb. 6, showed that Kamada’s IV-AAT demonstrated a trend towards improvements in multiple clinical outcomes, including days on mechanical ventilation post-transplant, pulmonary function at week four and week 48 post-transplant, and six-minute walk test.
Although the human sample is small, Kamada appears to be cautiously optimistic about the trials thus far.
The study, conducted at the Rabin Medical Center–Beilinson Hospital in Israel under the leadership of Dr. Mordechai R. Kramer, director of the center’s Institute of Pulmonary Medicine, is being conducted in collaboration with Shire plc, now owned by Japan’s Takeda. Kramer is running the lung transplant program in Israel, where close to 200 lung and heart lung transplants were performed.
“Decreasing post-transplantation mechanical ventilation duration of lung-transplanted patients and reducing proportion of PGD [primary graft dysfunction] are meaningful clinical targets that may also reduce long-term complications, such as chronic rejection,” says Kramer. “Lung transplant recipients suffer from numerous post-operative complications, prolonged hospitalization duration and high mortality rates.
“I am encouraged by the interim results of this study, and believe that further advanced powered studies are warranted to validate these meaningful signals of improvement.”
According to the International Society for Heart and Lung Transplantation (ISHLT), PGD is associated with higher rate of complications such as chronic rejection and higher mortality rate.
Amir London, CEO of Kamada, stated, “We are pleased by these interim results and look forward to top-line data from this study, expected in the second half of 2019. This study is a reflection of Kamada’s dedication to the lung transplant community, a patient group with a significant unmet medical need.”
“Moreover, our complementary ongoing AAT research programs in graft vs. host disease (GvHD) and organ preservation demonstrate the broad potential utility and scalability of our drug and its unique mechanism of action,” London continued. “We believe that this franchise of transplantation-related AAT treatments represents a significant market opportunity for Kamada.”
These interim data will be presented at the International Society for Heart and Lung Transplantation 2019 Annual Meeting and Scientific Sessions, from April 3-6, in Orlando, Fla.
The Phase 2 proof-of-concept trial is a randomized, open-label study of 30 lung transplant patients to evaluate the safety and efficacy of IV-AAT to prevent lung transplant rejection and assess impact on pulmonary function measured by FEV1 compared with standard-of-care treatment (SOC).
Patients were randomized 2:1, with 20 patients assigned to the treatment group receiving IV-AAT in combination with SOC (AAT+SOC), and 10 patients assigned to the control group receiving only SOC. This is a two-year study, with one year of treatment and one year of follow-up.
In May 2018, the last patient enrolled in the study completed one year of treatment and began the one-year follow-up period. This most recent interim report summarizes data from the one year treatment period for all patients in the study.
None of the adverse events (AEs) or serious adverse events (SAEs) observed to date were considered to be related to treatment with IV-AAT, according to the study. Acute rejection rates and pulmonary infections were similar in both study groups. Events of acute rejection were observed in five AAT+SOC patients (26 percent) vs. four events in three SOC patients (30 percent), and pulmonary infections were observed in 10 AAT+SOC patients (53 percent) vs. five SOC patients (50 percent).
Pulmonary function showed a trend towards improved FEV1 percent of predicted value in the AAT+SOC group at week four, and week 48 post-transplantation compared to the SOC group (at week four: 59.4 ± 3.8 for AAT+SOC vs. 45.6 ± 3.3 for SOC; at week 48: 58.0 ± 13.0 for AAT+SOC vs. 52.1 ± 3.9 for SOC).
FEV1 indicates the volume of air forcefully exhaled within the first second of exhalation. Low FEV1 values indicates the presence of breathing disorder and correlates with the severity of the disease.
When compared to SOC, treatment with AAT+SOC demonstrated a trend towards a lower percentage of patients with PGD grade 3 on day three (15 percent of the patients with AAT+SOC vs. 30 percent of the patients with SOC treatment), and a shorter mechanical ventilation time post-surgery (median of one day with AAT+SOC vs. 4.5 days with SOC treatment). In addition, the AAT+SOC group demonstrated a trend towards improved Six Minute Walk Test (6MWT) results at the end of week 48, compared to the SOC group (445±115 meters for AAT+SOC vs. 371±144 meters for SOC).
Throughout the one-year treatment period, 44 adverse events (AEs) were reported in the SOC group, while a total of 107 AEs were reported in the AAT+SOC group. Out of the 44 AEs in the SOC group, 12 were serious adverse events (SAEs), while out of the 107 AEs in the AAT+SOC group, 31 were SAEs.
During the one-year treatment period of the study, five patients in the AAT+SOC group and two patients in the SOC group died. During the follow-up period, to date, three additional patients from the AAT+SOC group have died. All deaths were considered as resulting from common transplant-related complications and unrelated to treatment with IV-AAT.
Lung transplantation is the last resort for patients who suffer from an end stage lung disease, Kamada reports. While survival rates are improving, there is a constant need for reducing acute and chronic rejection rates.
Long-term graft and patient survival are limited by both acute and chronic allograft rejection, with a median survival of just over six years. Fully one-third of all lung transplant recipients experience acute rejection in the first year, and 40 percent will develop chronic rejection within the first five years. Current treatment options, such as immunosuppressants, have limited efficacy and can have significant adverse side effects and co-morbidities.