Lodotra^™ – Clinical Results

Nitec has conducted a pivotal phase 3 study, the Circadian Administration of Prednisone in RA-1 (“CAPRA-1”) study to investigate the efficacy of Lodotra^™ in the treatment of rheumatoid arthritis (RA). CAPRA-1A was a 12 week, double-blind, positive-controlled study in Europe with 288 RA patients comparing the night-time administration of Lodotra^™ with the morning administration of standard immediate release prednisone at the same individual dose (average dose of approximately 6 mg). All patients were on combination therapy and were also prescribed DMARDs and NSAIDs if needed. CAPRA-1A was followed by a 9-month, open-label extension study with 249 RA patients (“CAPRA-1B”).

The results of this double-blind study showed that the evening administration of Lodotra^™ was superior to an identical dose of immediate release prednisone in reducing the duration of morning stiffness. The median relative change in duration of morning stiffness of the joints from baseline in patients taking Lodotra^™ was approximately 34 % (mean reduction of approximately 23 %) after 12 weeks and approximately 50 % after the open-label phase. Importantly, Lodotra^™ reduced IL-6 levels by approximately 29 % (relative median change) while corresponding levels following standard prednisone remained constant. In addition, Lodotra^™ was as effective as standard treatment for DAS 28, ACR 20 and all other efficacy parameters investigated. Lodotra^™ was as safe and as well tolerated as immediate release prednisone tablets.

In the open-label extension to this study, patients previously assigned to the immediate release product in the previously double blind phase but then switched to Lodotra^™ also experienced both a reduction in the duration of morning stiffness as well as a reduction of IL-6 similar to the treatment effect of the double-blind phase. All patients, those previously assigned and newly assigned to Lodotra^™, exhibited further positive trends in the improvement of morning stiffness over the 9-month course of this extension study. A 40 percent reduction in IL-6 levels also corresponded to improvements in the duration of morning stiffness following daily administration of Lodotra^™ in the evening.

Second phase 3 study for US Approval
In order to obtain FDA approval to market Lodotra^™ as a treatment for the signs and symptoms of RA including morning stiffness, Nitec is conducting a second pivotal phase 3 trial, the Circadian Administration of Prednisone in RA-2 (CAPRA-2) study. In CAPRA-2, Lodotra^™ administered at 10pm is compared to placebo given at the same time. The CAPRA-2 data will be used to complement the pivotal safety and efficacy data used for the European filing and approval. The primary endpoint of CAPRA-2 will be the ACR 20 response rate, defined as at least a 20 % improvement in a number of disease defining criteria such as tender joint count, swollen joint count and patient assessment of pain. Nitec must meet this endpoint with statistical significance versus placebo, in order to gain a label in the US indicating the treatment of the signs and symptoms of RA. In addition, the absolute change in the duration of morning stiffness and the severity of morning stiffness will be assessed. The FDA has indicated that if CAPRA-2 demonstrates a significant reduction of morning stiffness, it would allow Nitec to include a specific morning stiffness claim in the label for Lodotra^™. By receiving the label indicating the treatment of the signs and symptoms of RA including morning stiffness, Lodotra^™ will be the only product with such a unique label, which Nitec expects to allow more effective marketing of Lodotra^™.

In CAPRA-2 patients will be randomized in a double-blind fashion to either Lodotra^™ 5 mg once a day or matching placebo for a treatment period of 12 weeks. The primary endpoint of the study will be the ACR 20 response rate with the absolute change in the duration of morning stiffness and the severity of morning stiffness being key secondary endpoints. Other secondary endpoints will include ACR 50 and ACR 70 response rates.

Nitec expects results from this second phase 3 in H2 2009.

Lodotra^™ in severe asthma
Nitec is conducting a phase 2 trial to demonstrate the ability of Lodotra^™ to treat severe asthma. The trial is expected to be a ten patient, six week open label trial with the same dosage of prednisone as standard treatment and will aim to demonstrate superiority over standard treatment in improving pulmonary function and asthma symptoms including a reduction of nocturnal awakenings. If the outcome of this study proves to be favourable, a pivotal phase 3 study is expected to be conducted thereafter to attain marketing approval of Lodotra^™ for the treatment of severe asthma in the EU and the US.

Lodotra^™ in polymyalgia rheumatica
Based on an approval of Lodotra^™ in RA, Nitec will discuss the requirements with the regulatory authorities for a label extension in polymyalgia rheumatica. Nitec expects to begin the necessary label extension trial within the next 12 months to investigate the ability of Lodotra^™ to treat PMR.