Apremilast first phase 3 results

[Fred]

Celgene today announced top-line results from the PALACE-1 study, the first of three pivotal phase III, randomized, placebo-controlled studies evaluating the Company’s novel, oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) in patients with psoriatic arthritis who had received an oral disease-modifying antirheumatic drug (DMARD), biologic therapy or had failed on an anti-tumor necrosis factor (TNF) agent. *Apremilast treatment in this study was used alone or in combination with an oral DMARD.

In the study, statistical significance for the primary endpoint of ACR20 was achieved for patients receiving apremilast. Patients in the active treatment arms also maintained significant improvements in arthritis-related endpoints, including ACR50 and ACR70 through week 24. Significant and sustained improvements in various measures of physical function were also observed in apremilast-treated patients.

The overall safety profile was consistent with previous experiences in the phase II program and tolerability was improved. Common side effects for PDE4 inhibitors have been gastrointestinal in nature. In the PALACE-1 study, gastrointestinal adverse events, upper respiratory tract infections, as well as headache, were no more common in apremilast-treated patients than in those receiving placebo.

The PALACE-1 study is ongoing and the study extension remains blinded until all patients complete week 52. Full data from this phase III study will be submitted for presentation at appropriate medical meetings.

Source: celgene.com

*Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, and other inflammatory cytokines. Elevation of cAMP also increases anti-inflammatory cytokines such as IL-10.

[Fred]

Celgene today announced that statistical significance for the primary endpoint of ACR20 at week 16 was achieved for patients receiving apremilast 20 mg and 30 mg BID in both the PALACE-2 & 3 phase III studies. Positive PALACE-1 data was previously reported. PALACE-2 & 3 are the second and third of three pivotal phase III, randomized, placebo-controlled studies evaluating the Company’s novel, oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) in patients with psoriatic arthritis who had received or failed oral disease-modifying antirheumatic drugs (DMARDs), and/or an anti-tumor necrosis factor (TNF) agent. In each of these studies, apremilast was used alone or in combination with oral DMARDs.

Patients in the active treatment arms also maintained statistically significant improvements in ACR20 through week 24. Consistent with PALACE-1, statistically significant and clinically meaningful responses in various measures of signs and symptoms and physical function were also observed in both studies in apremilast-treated patients through week 24.

The overall safety profile was consistent with previous experiences in the PALACE-1 study and phase II program. Tolerability was improved over the phase II program.

The PALACE-1, 2 & 3 studies are ongoing, and the study extensions remain blinded to investigational sites until all patients complete week 52. Full data from these phase III studies will be submitted for presentation at appropriate medical meetings.

The NDA submission, based on the combined PALACE-1, 2 & 3 studies for PsA, is expected in the first quarter of 2013. A combined MAA submission for PsA and moderate-to-severe psoriasis in Europe is also planned for the second half of 2013.

In a Phase II trial (BCT-001) in patients with Behcet’s disease (BD), a rare inflammatory disorder and area of high unmet medical need, statistical significance was demonstrated for the primary endpoint of the number of oral ulcers at day 85 between apremilast 30 mg BID and placebo. Statistical significance and clinically meaningful responses in other manifestations of BD were also achieved. The overall safety and tolerability profile was consistent with previous experience in other studies with other patient populations. Behcet’s disease is a chronic inflammatory disorder of unknown cause characterized by recurrent oral and genital ulcers; prevalence of BD is highest in the Eastern Mediterranean, the Middle East and East Asia, but is classified as a rare or “orphan” disease by the NIH in the United States and EURODIS in Europe. The Company is currently exploring opportunities to submit for an indication in Behcet’s disease in a number of countries.

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[Fred]

UPDATE:

Celgene International Sàrl, a subsidiary of Celgene Corporation (NASDAQ: CELG) today presented the results from PALACE-1, the Company’s first Phase III study in psoriatic arthritis, at the American College of Rheumatology annual meeting in Washington, D.C.

The company previously announced statistical significance for the primary endpoint of ACR20 for patients receiving apremilast in the PALACE-1 study, the first of three pivotal phase III, randomized, placebo-controlled studies evaluating the Company’s novel, oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) in patients with psoriatic arthritis who had received oral disease-modifying antirheumatic drugs (DMARD) and/or biologic therapy and/or had failed on an anti-tumor necrosis factor (TNF) agent. Apremilast treatment in this study was used alone or in combination with oral DMARDs. PALACE-1 is the first phase III study demonstrating statistical significance in a psoriatic arthritis patient population that included both prior biologic exposure (23.6%) and biologic failures (9.3%).

In the study, apremilast demonstrated statistically significant and higher ACR20 responses at week 16 in patients receiving either apremilast 20 or 30 mg BID monotherapy (31.5% and 50.8% respectively vs. 10.5% for placebo; P<0.05 and P≤0.0001), with no meaningful advantage to adding oral DMARDs to apremilast. A higher ACR20 response at week 16 was also demonstrated in biologic-naïve subjects receiving apremilast 30 mg BID monotherapy compared with placebo (59% vs. 12%; P<0.005).

“The results of this first phase III trial of apremilast are encouraging for both physicians and patients as a potentially effective and safe oral therapy for psoriatic arthritis patients,” said Arthur F. Kavanaugh, M.D., Professor of Clinical Medicine at the University of California, San Diego and Director of the Center for Innovative Therapy at the University.

Across the entire study population, statistically significant changes in reducing signs and symptoms of PsA, as measured by the primary endpoint of ACR20 at week 16, were achieved for patients receiving apremilast 30 mg BID vs. placebo (41.01% vs. 19.4%; P≤0.0001). This was further supported by a robust and consistent response (P≤0.0001) across all arthritis-related secondary endpoints, including ACR50, ACR70, DAS-28, good or moderate EULAR response achievement and CDAI at week 24. Statistically significant results were also demonstrated in measures of physical function (HAQ-DI, SF-36 physical function domain score) at week 16 (P=0.0015 and P=0.0049 respectively) and these results were maintained at week 24.

The overall safety profile was consistent with previous experiences in the phase II program. Importantly, no opportunistic infections (including TB) or lymphoma were observed through week 24, and there was no increase in risk of cardiovascular events. Apremilast was generally well tolerated. The majority of AEs (>95%) were mild or moderate, with serious AEs and discontinuations due to AEs similar across all treatment arms.

An NDA submission to the U.S. Food and Drug Administration, based on the combined PALACE program for PsA, is expected in the first half of 2013. The sNDA submission for psoriasis is expected to follow in the second half of 2013. A combined MAA submission in Europe is also planned for the second half of 2013.

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[Fred]

UPDATE:

Celgene International Sàrl, a subsidiary of Celgene Corporation (NASDAQ: CELG) today announced that statistical significance was achieved for the primary endpoint of ACR 20 at week 16 for patients receiving apremilast 20 mg and 30 mg BID monotherapy in PALACE 4. PALACE 4 is the fourth randomized, placebo-controlled study evaluating the Company’s novel, oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) in patients with psoriatic arthritis. This is the first Company-sponsored trial studying patients who had not previously received an oral disease-modifying antirheumatic drug (DMARD).

“Despite recent advances in the treatment of psoriatic arthritis, there remains a significant need for more oral DMARD treatment options for DMARD-naïve patients,” said Randall Stevens, VP of Clinical Research and Development for Inflammation & Immunology. “PALACE-4 is now the fourth major randomized apremilast Phase III study to provide promising results for patients with psoriatic arthritis.”

Patients on apremilast also achieved a statistically significant benefit over placebo in key secondary endpoints, as demonstrated in various measures of physical function and signs and symptoms, including enthesitis.

No new safety and tolerability signals identified, with fewer AEs and SAEs reported than in PALACE 1, 2&3. Importantly, in PALACE 4, no systemic opportunistic infections (including TB) or lymphoma were observed through week 24, and there was no increase in risk of cardiovascular events. The most common AEs in PALACE 4 (≥5%) were nausea, diarrhea and headache.

The PALACE 4 study is ongoing and the study extension remains blinded until all patients complete week 52. Full data from this phase III study will be submitted for presentation at appropriate medical meetings.

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