FDA, Clinical Trial Updates: Biogen, Roche, Salix, Cell Therapeutics, Pfizer

Below is a summary of updates to the BioMedReports.com database of over 200 entries included in the FDA and Clinical Trial Calendars. The FDA Calendar includes companies with pending new drug, biological agent, or medical device new product decisions at the FDA sorted by their PDUFA decision deadline dates while the Clinical Trial Calendar encompasses pending clinical trial results (with a focus on late-stage, Phase 3 trials), pending new submissions to the FDA (e.g. NDA, BLA, 510k, PMA, sNDA, sBLA filings), and pending re-submissions to the FDA for complete response rulings by the agency which require more information before an approval can be granted.

On 5/19/09, Biogen (NASDAQ:BIIB) and Genentech (acquired by Roche) (RHHBY.PK) announced that the companies submitted two supplemental Biologics License Applications (sBLAs) to the FDA for Rituxan (rituximab) plus standard chemotherapy for people with previously untreated or treated chronic lymphocytic leukemia (CLL). The companies will request a priority review, and if granted, anticipate the FDA will make a decision within six months for an estimated PDUFA decision date of 11/19/09.

The applications are based on positive results from two of the largest global Phase 3 clinical trials conducted in patients with CLL, which showed that Rituxan plus standard chemotherapy for CLL extended the time patients lived without the cancer advancing (progression-free survival or PFS) compared to those receiving chemotherapy alone.

In CLL8, previously untreated patients who received Rituxan plus chemotherapy had a 69% improvement in PFS (41 percent risk reduction, hazard ratio=0.59; p<0.0001; 95% confidence interval: 0.44,0.72) compared to those who received chemotherapy alone. In REACH, patients whose cancer relapsed after previous treatment had a 54% improvement in PFS after receiving Rituxan plus chemotherapy compared to patients receiving chemotherapy alone (35 percent risk reduction, hazard ratio=0.65; p=0.0002; 95% confidence interval: 0.51, 0.82).

Salix Pharma (NASDAQ:SLXP): A U.S. advisory panel on Tuesday rejected a Debiovision Inc drug to treat a dangerous type of bleeding in the esophagus. The FDA advisory committee voted 14-0 that current data did not show that the benefits of the drug, Sanvar (vapreotide), outweighed potential risks. SLXP is the U.S. marketing partner for Swiss-based Debiopharm, which filed its complete response to the FDA on 11/4/08 in response to an earlier approvable letter for Sanvar. The immediate release formulation of Sanvar, a somatostatin analogue, is used in the treatment of a condition known as acute esophageal variceal (veins) bleeding.

Cell Therapeutics (NASDAQ:CTIC): CTIC released updated safety data on 5/19/09 from its pixantrone Phase 3 EXTEND clinical trial which demonstrated the effectiveness of pixantrone in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL) for whom anthracycline-related drugs are typically not to be used due to the increased risk of cardiac failure.

As noted during the presentation of Craig Philips, President of CTI,

The standard chemotherapy regimen (CHOP) for this disease exposes patients to less than or equal to 300mg/m2 of doxorubicin, a dose at which 5.6% of patients are expected to develop congestive heart failure (CHF). At cumulative doses of doxorubicin in excess of 600mg/m2, 48% of patients develop CHF.

At a cumulative total doxorubicin equivalent exposure of > 600mg/m2, the frequency of CHF among PIX 301 recipients was 4% compared to 48% reported for doxorubicin.

Pfizer (NYSE:PFE): PFE announced on 5/19/09 that the addition of Lyrica (pregabalin) capsules to other generalized anxiety disorder (GAD) treatments significantly improved the symptoms of the condition in patients who responded only partially to previous treatments, according to a study presented at the American Psychiatric Association annual meeting. In this study, patients treated with Lyrica showed significant improvements in both their psychological and physical symptoms of anxiety. According to the Company's press release, this is the first large, placebo-controlled trial to demonstrate the efficacy of an add-on therapy strategy in patients who had failed to respond to two different courses of GAD mono-therapy with a SSRI, SNRI, or benzodiazepine.

The study found that patients treated with Lyrica in addition to their baseline SSRI/SNRI therapy had a significantly greater improvement in overall anxiety symptoms as well as individual psychological and physical symptoms compared to baseline therapy alone as measured by the Hamilton Anxiety Scale (HAM-A), an interview scale that measures the severity of a patient's anxiety. Over the eight week treatment period, patients receiving add-on Lyrica therapy had, on average, an anxiety score that was 1.2 points lower on the HAM-A compared to baseline therapy alone (P=0.012). Significantly more patients receiving add-on Lyrica treatment (50 percent) showed at least a 50% reduction in their anxiety symptoms compared to SSRI/SNRI treatment alone (37 percent) (P=0.023). Lyrica was also shown to be well tolerated as an add-on therapy in this study.

Disclosure: No positions.

Comments

[Bill Ronaldson:]

57 patients on Rituxan have developed PML. Here is more on that development: www.newsinferno.com/ar...

May 20 11:39 PM

[Dan Eramian:]

We read your references to pixantrone and have received a few calls asking for a better explanation of the information we released at the BIO conference this week in Atlanta regarding a historical comparison of cardiac congestive events on the PIX301 study compared to the expected dose dependant incidence with standard doxorubicin dosing.

It is important to note that the comparator arm did not contain treatment with a class of drugs known for cardiac side effects (with the exception of 4/68 patients who received mitoxantrone). Thus the only way to put the safety data with pixantrone in perspective is to provide, solely for illustrative purposes, the numerical events of CHF (irrespective of relationship to drug) by total doxorubicin equivalent exposure, and see how it would stack up based on literature review.

Here’s some background relevant literature:

JCO 1995, 13:2530-2539, Sonnenveld et al. Study of CNOP Vs CHOP in 148 elderly patients >=60 years of age with aggressive NHL. Only 31% (23 patients) of CNOP and 45% (33 patients) of CHOP patients received all 6 cycles of therapy (for CHOP that would be 300mg/m2 of doxorubicin). LVEF declines of >=15% occurred in 10/22 CHOP patients treated with 300mg/m2 who had LVEF’s measured, and who got 6 cycles (300mg/m2 of dox). 4/33 patients who received 6 cycles of CHOP developed CHF (12%). On intent to treat 4/74 = 5.5%. Thus at standard CHOP exposure of 300mg/m2 – 5.5% develop CHF on an intent to treat basis.

NEJM 1998, 319:745-752 Speyer et al. Study of FDC (flurouracil, doxorubicin, cyclophosphamide) with or without ICRF-187 (an investigational cardio-protectant agent) in 92 women with metastatic breast cancer. LVEF declines of 7% from baseline were observed in the 250mg/m2 to 399mg/m2 group, with 16% declines in the group receiving between 400mg/m2 and 499mg/m2. CHF developed in 11/46 patients (24%). Their median doxorubicin exposure was 397mg/m2.

Cancer 2003, 97:2869-2879, Swain et al. CHF in patients with doxorubicin treatment- retrospective meta-analysis of 3 trials. In this publication women with metastatic breast cancer treated with FDC in 3 separate trials were reviewed and combined to examine the dose-dependent increase in CHF at various levels of total doxorubicin exposure. Overall 178,500mg/m2 was administered to 630 patients (283mg/m2 dox exposure) 32/630 patients developed CHF (5.1%). These data are consistent with the other studies reporting approximately 5% rates of CHF in the standard CHOP dose of 300mg/m2. As noted in Swain, the majority of CHF events occurred at or above a total of 500mg/m2. Using a Kaplan Maier estimation, Swain developed a table estimating 5% incidence at 400mg/m2, 16% at 500mg/m2, 26% at 550mg/m2 and 48% at 700mg/m2.

Importantly in each of these reviews (and well documented in all the literature as well as the doxorubicin drug label), cardiac toxicity is a linear cumulative life-time dose dependant side effect of this class of agents.

Since PIX301 was not a randomized trial against standard doxorubicin, and given that patients had a median of ~300mg/m2 of prior doxorubicin exposure before starting on pixantrone, these patients, based on the literature cited, would be expected to have a significant frequency of CHF events given the median cumulative doxorubicin equivalent exposure of 535mg/m2 (>26% CHF and >50% declines in LVEF >20% from baseline according to historical literature) if this were standard doxorubicin.

The table presented at BIO (and noted in our press release) was an illustrative representation of the number of reported CHF events at various total cumulative doxorubicin equivalent exposure for standard 300mg/m2 levels upward to in excess of 650mg/m2. We do not present this as definitive clinical evidence of lower cardio toxicity, and some have suggested that a randomized comparison to doxorubicin would be the gold standard for demonstrating a lower incidence of cardiac damage. Such a trial has completed its 2 year follow up period (CHOP-R Vs CPOP-R, n=124 patients). This study extensively measured (every 2 cycles x 6 cycles, then every 3 months for 2 years) cardiac function which is evaluated by an independent cardiologist blinded to treatment assignment. These data will be included in the NDA safety update, and we hope to have it presented at this year’s ASH meetings in December.

We hope this information, and the new efficacy and safety information being presented at ASCO will further clarify the unique risk-benefit profile pixantrone has over standard anthracyclines and the impressive efficacy in patients with relapsed/refractory aggressive NHL.

Cell Therapeutics

May 21 08:06 PM

[JKM:]

Cell Therapeutics, Inc. has added a news release to its Investor Relations website.
Title: Pixantrone Significantly Increases Complete Remissions, Overall Response Rates, Frequency of Durable Remissions and Progression Free Survival in Patients with Relapsed and Refractory Aggressive Non-Hodgkin's Lymphoma
Date: 6/1/2009 2:00:00 PM
For a complete listing of our news releases, please click here
investors.celltherapeu...

Jun 01 02:16 PM