Clinical Trials

* On September 4, 2014, Kamada, a plasma-derived protein therapeutics company focused on orphan indications, announces results from the complete analysis of the European Phase 2/3 clinical study of its inhaled Alpha-1 antitrypsin (AAT) therapy for the treatment of Alpha-1 antitrypsin deficiency (AATD). Following a complete analysis of the study data, the Company confirms that the study’s primary endpoint of “Time to the first moderate or severe exacerbation event” did not show a statistically significant difference between inhaled AAT and placebo in the Intent-to-Treat (ITT) population, as reported in May 2014. The Company also reports that the study did not show statistically significant differences between inhaled AAT and placebo in the secondary exacerbation endpoints measured in the ITT population. Despite not meeting the primary or secondary endpoints for the ITT population, lung function parameters, including Forced Expiratory Volume in One Second (FEV1) % of Slow Vital Capacity (SVC), FEV1 % predicted, FEV1 (liters) and Diffusing capacity (DLCO), which were collected to support safety endpoints, showed concordance of a potential treatment effect in the reduction of the inflammatory injury to the lung that is known to be associated with a reduced loss of respiratory function. These effects were most apparent in the frequently exacerbating patients (the “Most Frequent Exacerbators”), who represented more than 70% of those enrolled in the study.

Notably, inhaled AAT therapy showed clinically relevant changes in various lung function measurements for the entire ITT population, as well as for the Most Frequent Exacerbators population, a few of which were statistically significant. This suggests evidence of therapeutic activity resulting in a clinically relevant and meaningful effect for the first time in studies of any AAT treatment. The importance of these findings should be viewed in the context of all existing intravenous (IV) AAT therapies, which obtained regulatory approvals on the basis of pharmacokinetic and safety data only. Safety data of inhaled AAT in this Phase 2/3 trial remains supportive and consistent with previous inhaled AAT studies conducted by Kamada, and continues to demonstrate a high safety and tolerability profile.

For the Primary Endpoint of “Time to the first moderate or severe exacerbation event,” the Survival Curve (Kaplan Meier Curve) and hazard ratio in the ITT population did not show a difference between the inhaled AAT group and the placebo group. Yet, the concordant clinical and functional differences observed with regards to changes in exacerbation events for primary and secondary endpoints in the Most Frequent Exacerbators provide an indication of therapeutic activity not detected in previous AAT clinical studies.

The primary endpoint of “Time to the first moderate or severe exacerbation event” in the Most Frequent Exacerbators suggested a favorable clinical difference between inhaled AAT treatment (n=67) and placebo (n=54), as reflected by the Survival Curve and hazard ratio 0.877 (95% CI 0.563, 1.364; p-value=NS[1]).

No differences were found for the ITT population between the groups for the secondary endpoint of “Time to first event-based exacerbation with a severity of mild, moderate or severe”, yet for the Most Frequent Exacerbators, the median time until the first event was longer in the inhaled AAT group compared with the placebo group. Hazard Ratio = 1.064 (95% CI 0.717, 1.578; p-value=NS).

Regarding the secondary endpoint of “Severity of the first exacerbation event” in the ITT population, the inhaled AAT group experienced a lower percentage of first severe (“Type 1”) exacerbation events compared with the placebo group (18.8% and 31.1%, respectively; p-value=NS). For the same exacerbation definition, a lower percentage of first severe exacerbation events was also observed in the Most Frequent Exacerbators compared with placebo (19.4% and 35.2%, respectively; p-value=NS) as well as for both severe and moderate exacerbation events compared with placebo (44.8% and 51.9%, respectively; p-value=NS). These differences were also evident in the event-based definition. In the ITT population, the percentage of the first moderate event was lower in the inhaled AAT group compared with the placebo group (56.5% and 63.9%, respectively; p-value=NS); in the Most Frequent Exacerbators the percentage of the first moderate exacerbation events was 15.1% lower in the inhaled AAT group compared with the placebo group, and the percentage of both moderate or severe first exacerbation events was 4.7% lower in the inhaled AAT group than in the placebo group. These findings were not statistically significant.

For the secondary endpoint of “Rate of exacerbation events as reflected by the number of event-based exacerbation events in the study,” there was no difference between the inhaled AAT group and the placebo group in the ITT population. There has been no difference for the number of severe exacerbation events in the study. However, for the Most Frequent Exacerbators there was a reduction of 10% in the inhaled AAT group compared with the placebo group in all types of exacerbation events (number of exacerbation events including mild/ moderate/ severe), a reduction of 13% in the number of moderate event-based exacerbations and a reduction of 12% in the number of moderate/ severe event-based exacerbations. These findings were not statistically significant.

With regard to lung function data in the ITT population that was measured under the safety endpoints, the FEV1 % of SVC, mean change from baseline in the inhaled AAT group at study week 50 showed a statistically significant increase compared with a decline in the placebo group (+0.34% and -1.17%, respectively; p-value=0.033).

Positive concordant clinical pattern trends were seen in all other lung function tests in favor of inhaled AAT in the ITT population.

For FEV1 % predicted, the placebo decline was more than two-fold greater than that in the inhaled AAT treated population (-1.37 vs. -0.509, respectively; p-value=NS). Similarly, FEV1 (liters) showed a steeper decline in the placebo group compared with the inhaled AAT group (-52ml and -25ml, respectively; p-value= NS).

The diffusing capacity (DLCO [mMol/min/Kpa]) in the inhaled AAT group declined less than in the placebo group (-0. 168 and -0.28, respectively; p-value=NS).

The inhaled AAT group of Most Frequent Exacerbators also showed favorable results across all lung function measurements. A statistically significant difference was seen for FEV1 % of SVC with an increase in the inhaled AAT group compared with a decline in the placebo group, as expressed by the mean change from baseline at week 50 placebo (+0.2251% and -1.68%, respectively; p-value=0. 0208). FEV1 % predicted declined less compared with the placebo group (-0.58 vs. -1.21, respectively; p-value=NS). FEV1 (liters) decreased less in the AAT group compared with placebo group (-18ml and. -51ml, respectively). These changes were not statistically significant at week 50, though concordant with other spirometry data. Diffusing capacity (DLCO [mMol/min/Kpa]) showed a greater decline in placebo patients compared with inhaled AAT patients (-0.336% and -0.206%, respectively). Although this change was not statistically significant at week 50, it remains concordant with the spirometry data. “Based on orphan designation of the drug, prior discussions held with the regulator, the strength of these data and the persistent unmet need in this orphan indication, we will advance our discussions with the European Medicines Agency with the intent to submit for conditional approval in order to bring our inhaled AAT to patients with AATD in Europe, and will initiate discussion with the FDA to determine a U.S. path for registration” noted David Tsur, co-Founder and Chief Executive Officer of Kamada. Recently, Kamada initiated a U.S. Phase 2 clinical trial with its inhaled AAT for AATD, and expects that the data from the European trial together with the data from the U.S trial will provide the foundation from which to develop its regulatory strategy for licensure in the U.S.

* On May 16, 2014, Kamada, a plasma-derived protein therapeutics company focused on orphan indications, announced preliminary top-line results from the Phase II/III pivotal clinical trial in Europe and Canada of the Company’s proprietary inhaled Alpha-1 Antitrypsin (AAT) therapy for the treatment of Alpha-1 Antitrypsin Deficiency (AATD or inherited emphysema). The endpoints selected for this trial were based on scientific advice from the European Medicines Agency (EMA) and include those deemed to be clinically meaningful, such as frequency, time to first, duration and severity of exacerbation events, among others. A preliminary analysis of the results indicates clinically meaningful signs for inhaled AAT efficacy as well as additional positive signs in specific study populations. In a very important secondary endpoint, frequency of severe exacerbation was approximately 50% lower in the AAT group versus placebo. With regards to the primary endpoint of “time to first moderate or severe exacerbation,” early data do not show differences between the two treatment groups. Forced Expiration Volume in one second (FEV1) data, a secondary and safety endpoint, indicated positive trends in improvement. Additionally, the data showed efficacy in certain subsets of patient populations. Safety data of inhaled AAT was supportive and consistent with previous reports and demonstrated a high safety and tolerability profile. Based on the initial review, the Company believes that some of the data may support the issuance of new patents for the product.The Company continues to analyze the data in accordance with the statistical plan and intends to release a more profound set of results in third quarter of 2014. The company believes the existing data support a regulatory filing in Europe, and will continue as planned to meet with the EMA according to the centralized procedure for licensure during the fourth quarter of this year. 

In August 2012 Kamada signed an exclusive agreement for the distribution of its inhaled AAT for the treatment of AATD in Europe and with Chiesi Farmaceutici S.p.A, a fully integrated European pharmaceutical company focused on respiratory disease and special care products. Under the agreement, Kamada is eligible to receive milestone payments of up to $60 million, subject to achievement of certain regulatory and sales targets. Recently, Kamada has initiated a U.S. Phase II clinical trial with its inhaled AAT for AATD, and expects that the data from the European trial together with the data from the U.S. trial will support licensure application in the U.S. and additional territories.