Dermatologic and Ophthalmic Drugs Advisory Committee Meeting

September 9, 2003

 

Draft Discussion Topics

                                                                                                                 

License # STN BL 125075/0             Efalizumab

                                                            Genentech, Inc.

 

Proposed Indication:                         For the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis

 

I.                Efficacy Outcomes

 

A.

Efalizumab was studied in four randomized, placebo, controlled phase 3 trials in patients with stable chronic moderate to severe plaque psoriasis. The primary efficacy assessment was the proportion of patients with >75% improvement in PASI score from baseline. The static physician’s global assessment (OLS) of “minimal” or “clear” was a secondary outcome.  At the end of a 12- week treatment period, the efalizumab-associated effect across studies ranged between 18-37% (absolute) by PASI 75 response criteria and 16-29% (absolute) by OLS assessment. 

 

1)     Please consider the strength of the information submitted by the sponsor demonstrating efficacy of efalizumab for the treatment of moderate to severe chronic plaque psoriasis.

 

 

B.

In Study ACD2058g, patients who responded to the first treatment course received a second 12-week treatment course upon relapse during the observation period.  Relapse was defined as loss of 50% or greater of the improvement in PASI score that had been obtained during the first treatment period.  Efalizumab was shown to recapture response in 31% of these patients. 

 

 

In Study ACD2059g, efalizumab-treated patients who responded to the initial treatment period were rerandomized to receive efalizumab or placebo for a second contiguous 12-week treatment period (without delay until relapse).  During this blinded treatment extension, 8% of patients randomized to continued treatment with efalizumab relapsed, (>50% loss of efalizumab treatment effect) while 92% did not relapse.   Also, 77% of this group maintained a PASI 75 response while 23% of patients failed to maintain PASI 75 improvement.   In comparison, approximately 20% of patients re-randomized to placebo (i.e., efalizumab withdrawal group) maintained PASI 75 while 80% failed to maintain PASI 75.  Most of the patients in the efalizumab-withdrawal group (67%) relapsed. 

 

 

1)     Please consider the potential therapeutic modes of use of efalizumab for chronic plaque psoriasis (i.e., continuous vs. intermittent treatment).

2)     Are additional studies warranted to investigate an intermittent efalizumab treatment regimen?

 

 

I.           Safety of Efalizumab

 

A.          Safety of long-term continuous treatment

 

The current paradigms for the treatment of psoriasis requiring systemic treatment include continuous long-term treatment and intermittent and/or rotational therapy. The latter is used in order to minimize exposure to individual agents and cumulative drug toxicities, e.g. hepatic toxicity with methotrexate and nephrotoxicity with cyclosporine.  Approximately 2400 patients received efalizumab weekly for 12 weeks of continuous treatment, 939 for 24 weeks of continuous treatment and 218 for one year of continuous treatment.

                                               

1)     Please consider the adequacy of the assessment of efalizumab safety for long-term continuous treatment.

 

2)     Please comment on the need for further long-term safety studies and highlight areas warranting specific long-term risk assessment (e.g. serious infections, malignancies or immunogenicity).

 

B.  Psoriasis-related adverse events

 

Treatment with efalizumab has been associated with the development of rapid worsening of psoriasis and psoriasis variants, namely psoriatic erythroderma, pustular psoriasis and guttate flares, sometimes requiring hospitalization.  Of over 2500 psoriasis patients treated with efalizumab, 19 (0.7%) had a psoriasis flare requiring hospitalization.  Such adverse events have occurred during treatment with efalizumab but were more common following discontinuation with efalizumab.  

 

1)     Please consider whether there are sufficient data at present to fully characterize this risk and to provide adequate guidance on the management of this risk?

 

2)     If not, please consider the optimal way(s) to generate additional data on the psoriasis-related risks.

 

C.        Arthritis and Other Inflammatory Adverse Events

 

There have been 15 cases of serious adverse events of arthritis representing 0.6% of the studied population including one case in association with other findings of inflammation (fever, cellulitis and positive ANA).  None of these cases has occurred during the placebo-controlled portion of the clinical trials. 

 

The overall proportion of patients with arthritis-related adverse events (including psoriatic arthritis, osteoarthritis and unspecified arthritis) during the placebo-controlled portions of the clinical trials were comparable between the placebo-treated patients (N=715, 2.2%) and patients treated with 1.0 mg/kg/wk efalizumab SC (N=1213, 2.4%).  However, there was a suggestion of a higher proportion of patients with arthritis-related adverse events (3.9%) among those who received the 2.0 mg/kg/wk dose of efalizumab (N=407).

 

Rare cases of other inflammatory adverse events have also been noted in association with the use of efalizumab [e.g. transverse myelitis (1 case), interstitial pneumonitis (2 cases), idiopathic hepatitis (1 case)].

 

 

1)         Please consider the adequacy of the data to fully characterize the potential risk of arthritis flares and other inflammatory adverse events. 

 

 

 

D.           Thrombocytopenia

 

Treatment with efalizumab has been associated with the development of clinically significant thrombocytopenia consistent with an immunologically mediated mechanism.  Overall, eight patients experienced platelet counts of less than 50,000 cells/mm3 (NCI-CTC Grade 3) and/or were hospitalized with thrombocytopenia.

1)     Has the sponsor generated sufficient data to fully characterize the potential risk of thrombocytopenia?  If not, please consider optimal ways to generate data on this risk.

2)     Please consider the adequacy of the data available for providing guidance on the management of this risk.

3)     If efalizumab is licensed, is monitoring of platelet counts indicated?      

 

             

 

 

 

 

III. Patient Population

 

1)     Please consider whether the overall risk-benefit comparison for use of efalizumab is favorable. 

 

2)     If the risk-benefit of efalizumab is favorable, please address the issues regarding the appropriate patient population. 

 

The sponsor has proposed that the indicated population be “adult patients with moderate to severe plaque psoriasis.”  Eligibility criteria permitted enrollment of individuals who had received prior systemic therapy or phototherapy as well as those naïve to such prior therapies.   The entry criteria excluded patients who did not have chronic (diagnosed for at least 6 months) plaque psoriasis at baseline.  Patients who were not clinically stable for at least 3 months were also excluded. 

 

a)         Should the use of efalizumab be limited to patients who have failed or had an inadequate response to phototherapy or systemic therapy?

 

b)         Should the use of efalizumab be limited to patients with moderate to severe plaque psoriasis who have stable, chronic disease? 

 

 

 

IV. Studies in Pediatric Populations

 

If the sponsor has shown that efalizumab is safe and effective for use in adults, please comment on the following issues.

 

 

1)     Should efalizumab be studied in pediatric patients with psoriasis?  If so, please discuss the optimal timing of such studies relative to accumulation of postmarketing safety data in adults. 

 

 

2)     What additional studied should be carried out in the pediatric population to fully assess safety and efficacy?  Please discuss the potential for loss of response to recall antigens and the response to childhood vaccines.

 

VI. Study of Efalizumab with Concomitant Systemic Antipsoriasis Therapies

 

In the clinical trials other systemic immunosuppressants and antipsoriasis medications were prohibited.  If a patient developed a psoriasis adverse event requiring alternative systemic therapy, he/she was to immediately stop the study drug. 

 

1)         Should efalizumab be studied in combination with other systemic antipsoriasis medications, either long term or for a defined period of overlap?  Please discuss.