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Pharmaceutical and Biotech News

Development News in 2011

(Page 2)

Pharmaceutical and Biotech News concentrates on events that mark progress (or failure) in the development of promising new treatments in challenging therapeutic areas.  These include key Phase 2 and Phase 3 clinical studies as well as evaluations and marketing authorizations by major regulatory agencies (such as the FDA and EMA). The areas covered are as follows:


Metabolic and inflammatory diseases and syndromes


Bacterial, viral and fungal infections

Neurological disorders (mostly stroke, multiple sclerosis and Alzheimer's disease)

In most cases, company announcements are dissected for pertinent facts and PR statements are either removed or placed in context. The title is linked to the company's public release.  Personal interviews and reviews by a variety of sites may be included.  Occasional commentary -clearly marked as such in red- is included as a counterpoint to the PR and to highlight specific compounds or clinical studies worthy of greater emphasis.  Marketed drugs, mentioned in these pages, will be linked, whenever possible, to their current US Package Inserts.


June 21, 2011

Positive data in a Phase 2 study with Roche's Vismodegib in advanced basal cell carcinoma (BCC)

The reason for including a brief analysis of these data of a phase 2 study (although the company is describing the study as "pivotal") is because of the compound being tested.  Vismodegib is a small molecure inhibitor of the Hedgehog pathway, a pathway involved in the tumorigenesis and a target in advanced malignancies.

The phase 2 study was a multicenter, open label, single arm, uncontrolled clinical trial.  The study enrolled 104 patients with advanced BCC including 71 patients with locally advanced BCC and 33 patients with metastatic BCC (mBCC).  The principal endpoint was objective response.  The study demonstrated that vismodegib substantially shrank tumors or healed visible lesions in 43% of patients with locally advanced BCC and 30% of patients with metastatic BCC. The median duration of progression-free survival (PFS) was 9.5 months. Since the study has been uncontrolled, it is really difficult to objectively evaluate these results.  One would have to wait for more advanced, fully controlled studies to estimate the possible utility of vismodegib.

June 14, 2011

Micromet's Blinatumomab Produces High Single-Agent Activity in Patients with Relapsed Acute Lymphoblastic Leukemia

Usually, I do not cover early studies (Phase 1 and 2).  But I am somewhat partial to Micromet's BiTE antibody technology, and these early results have captured my attention.  BiTE stands for "Bi-specific T-cell Engagers" and describes antibodies that bind to specific targets on malignant cells and also to the CD3 receptor of T-cells, sequestering them to the site of the tumor or type of cell/

Blinatumomab (MT103) is a BiTe antibody binds to the CD19 receptor of B-cells and to the CD3 receptor of T-cells.  It is being investigated in non-Hodskins Lymphoma, in acute lymphoblastic leukemia (ALL), in lung and gastrointestinal cancers.  The recent announcement concerned interim results of a phase 2 trial in relapsed ALL.  The study is expected to enroll 25 patients.  It is investigating the effects of two doses 15 and 30 μg/m²/day by continuous intravenous infusion.  The interim results, 9 of 12 patients showed either full or full hematologic remission (CR or CRh).  Of the patients in this study, 4 with genotypes associated with poor outcome, achieved full (CR or CRh) remission. 

May 27, 2011

FDA approves Optimer's fidaxomicin (Dificid®) for the treatment of  Clostridium difficile-Associated Diarrhea (CDAD)

Fidaxomicin (Dificid®) belongs to a new class of narrow-spectrum macrocyclic antibiotics (compounds that include a ring of at least 7 atoms).  It is poorly absorbed, resulting in topical, non-systemic exposure.  It affects mainly the pathogenic Clostridium difficile without disrupting the rest of the intenstinal flora.  It works by inhibiting the RNA polymerase of the target bacterium.

Optimer performed two pivotal studies with fidaxomicin in a total of 584 patients with CDAD.  Both were randomized (1:1), double-blind, multicenter, actively-controlled, noninferiority trials. The control agent was vancomycin and the non-inferiority delta was set at 10%.  Both trials compared 10 days of fidaxomicin at 200 mg orally bid to 10 days of vancomycin 125 mg orally qid in subjects with CDAD. Randomization was assisted by stratification according to prior CDAD episode.  Two strata were defined: 1) no prior episode in the last 3 months or 2) a single prior episode in the last 3 months. In both studies, the cure rate with fidaxomicin was similar to that of vancomycin (88% vs. 86%; 88% vs. 87%).  However, fidaxomicin was superior to vancomycin in global cure which is defined as cure with no recurrence at follow-up (70% vs. 57% ; 72 vs. 57%).

May 13, 2011

FDA approves Merck's boceprevir (Victrelis®) for the Treatment of Hepatitis C in Patients with Compensated Liver Disease

In fact, the FDA-approved indication is quite narrow,  Boceprevir (Victrelis®), a protease inhibitor, has been approved for the treatment of chronic hepatitis C (CHC) genotype 1 infection (which is usually difficult to treat), in combination with peginterferon alfa and ribavirin, in adult patients (≥18 years of age) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The safety and effectiveness of Victrelis was evaluated in two phase 3 clinical trials that enrolled approximately 1,500 adult patients. In these multicenter, double-blind and placebo controled studies, the patients were randomized into three groups.  One of the groups received placebo plus peginterferon-ribavarin for 44 weeks, the 2nd received boceprevir plus peginterferon-ribavarin for 44 weeks and the third received boceprevir plus peginterferion-ribavarin for 24 weeks, with the patients positive for HepC mRNA receiving placebo plus peginterferon-ribavarin for an additional 20 weeks.

Both trials showed a significantly higher sustained virologic response (No dectetable virus, with a possibility of relapse at below 2%) in the treatment arm (66-67%) when compared to placebo (21-40%). Common adverse events were anemia and dysgeusia. 

May 6, 2011

Overall Survival Benefit in the Intergroup Phase III Study (CALGB 100104) of Revlimid® (Lenalidomide) As Continuous Therapy for Patients with Multiple Myeloma following Autologus Stem Cell Transplantation

Revlimid® (lenalidomide) is a derivative of thalidomide marketed by Celgene for the treatment of previously treated patients with multiple myeloma and patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality. It is not indicated for patients newly diagnosed with multiple myeloma.

Researchers in the Cancer and Leukemia Group B (CALGB) -a research group sponsored by the National Cancer Institute- announced data from the ongoing study of Revlimid® as continuous therapy in myeloma (CALGB 100104) at the 2011 International Myeloma Workshop in Paris, France.

The Phase 3 CALGB 100104 clinical trial is a randomized, double-blind study of maintenance therapy with Lenalidomide (CC 5013) or placebo following autologous stem cell transplantation (ASCT) for multiple myeloma.  The study accessed 568 patients in 46 investigative sites. The independent Data and Safety Monitoring Committee (DSMC) conducted a planned interim analysis in November 2009 which included 418 pts, 210 randomized to lenalidomide and 208 to placebo. This analysis led to the announcement the study had met its primary endpoint and was subsequently unblinded. The data reported in Paris are derived from a continuing analysis of the subjects post-unblinding through April 2011.

As of April 2011, at a median follow-up of 28 months, patients receiving continuous lenalidomide following ASCT demonstrated a statistically significant improvement in overall survival (OS), with an OS rate of 90% (208/231) compared to 83% (190/229) for patients randomized to receive placebo (unadjusted p=0.018) hazard ratio 0.51 (95% CI = 0.26 to 1.014), despite nearly 80% (86/110) of patients crossing over to receive continuous lenalidomide at the time of study unblinding. Additional analyses of the original OS data at time of study unblinding demonstrated an OS rate of 94% (218/231) in the continuous lenalinomide arm compared to 89% (204/229) in the placebo arm (p=0.05). At a median follow-up of 28 months, the median time to progression (TTP) was significantly higher for the lenalidomide arm at 48 months versus the median TTP of 30.9 months for the placebo arm (p<0.0001) HR 0.44 (95% CI = 0.32 to 0.60). This translated to a 56% reduction in the risk of disease progression in the lenalidomide arm.

In prospectively defined subgroup analyses, TTP was significantly higher in all subgroups of patients that received continuous lenalidomide post ASCT. Within these subgroups TTP was longest in the group of patients that received lenalidomide both as induction therapy and continuous therapy following ASCT. Also, at a median follow-up of 28 months, the median event-free survival for patients in the lenalidomide arm was 43.4 months, versus 30.9 months in the placebo arm (p<0.0001) with an estimated HR of 0.51 (95% CI = 0.38 to 0.68) In this Phase III, controlled, double-blind, multi-center study, newly diagnosed multiple myeloma patients who achieved at least stable disease (SD) following autologous stem cell transplant (ASCT) were randomized to receive continuous daily treatment with lenalidomide 10 mg (n=231) or placebo (n=229) until relapse.

The most common grade 3-4 adverse events experienced by patients receiving lenalidomide or placebo in the study were neutropenia (43% 89/208 vs. 9% 17/197), thrombocytopenia (13% 26/208 vs. 4% 7/197) and infections (16% 33/208 vs. 5% 11/197). There were no grade 5 hematologic adverse events. The rate of grade 5 non-hematologic adverse events was similar between the two arms of the study (1% 3/208 vs. 2% 3/197). An increase in second primary malignancies (SPMs), mainly hematological malignancies, was observed in patients receiving lenalidomide compared to patients receiving placebo. However, the event free survival analysis, where SPM was included as an event, in addition to death and progression, demonstrated that there was no significant impact of SPMs on the observed TTP or OS benefit.

In addition to data from the CALGB 100104 study, Celgene announced data from additional studies of lenalinomide in multiple myeloma as well as a combined analysis of the use of lenalidomide as maintenance treatment in this disease.

April 11, 2011

Biogen Idec Multiple Sclerosis Drug, BG-12 (dimethyl fumarate) Achieves Endpoints in Placebo-Controlled Phase 3 Study


Biogen Idec announced top-line results from DEFINE, the first of two pivotal Phase 3 clinical trials designed to evaluate the investigational oral compound BG-12 (dimethyl fumarate) as a monotherapy in people with relapsing-remitting multiple sclerosis (RRMS). BG-12 is a methyl ester of fumaric acid and has been used in the treatment of psoriasis. During the investigation of the properties of this molecule, it was found to have immunomodulatory and neuroprotective effects.  A phase 2 study in multiple sclerosis did show that patients treated with BG-12 developed significantly fewer brain lesions than the controls after a period of 24 weeks.

The DEFINE (Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS) clinical study was pivotal (Phase 3) randomized, double-blind, placebo-controlled, dose-ranging study to determine the efficacy and safety of BG-12 in approximately 1,200 people with RRMS. The study evaluated two doses of BG-12: 240 mg twice a day and 240 mg three times a day. The primary objective was to determine if BG-12 is effective in reducing the proportion of relapsing patients at two years. Secondary endpoints included (a) reduction in the number of new or newly enlarging lesions as measured by MRI; (b)reduction in annualized relapse rate; (c) reduction of disability progression as measured by the Expanded Disability Status Scale (EDSS); and (d) the safety and tolerability of BG-12.

Results showed that 240 mg of BG-12, administered either twice or three times a day, met the primary study endpoint, demonstrating a statistically significant reduction (p<0.0001) in the proportion of patients with RRMS who relapsed at two years compared with placebo. Both doses of BG-12 also met all of the secondary study endpoints, providing a statistically significant reduction in annualized relapse rate, in the number of new or newly enlarging lesions, and in the rate of disability progression as measured by the Expanded Disability Severity Scale (EDSS) at two years.

Topline data also showed that BG-12 demonstrated a favorable safety and tolerability profile. The overall incidence of adverse events and serious adverse events was similar among the placebo group and both BG-12 treatment groups. The safety profile was consistent with what was seen in the published Phase 2 study of BG-12.

BG-12 received Fast Track designation from the U.S. Food and Drug Administration (FDA) in 2008.  Since the DEFINE clinical study has been a placebo-controlled trial, any optimism should be guarded. One must await the results of the follow-up study (CONFIRM) to see if BG-12 represents an advance in the state of the art in multiple sclerosis.  The CONFIRM Phase 3 clinical study is currently underway. This randomized, double blind, actively and placebo- controled trial is evaluating BG-12 and a recently approved drug in MS, glatiramer acetate (Copaxone®, Teva Pharmaceuticals)  against placebo utilizing similar endpoints as those used in the DEFINE study. Results from CONFIRM are expected in the second half of 2011.

March 14, 2011

Aflibercept Fails as 2nd-Line Treatment in Combination with Docetaxel of Non-Small Cell Lung Cancer

Aflibercept, developed jointly by Regeneron Pharmaceuticals  and Sanofi-Aventis, is a fusion protein  that combines portions of human VEGFR1 and VEGFR2 [Vascular Endothelial Growth Factor (VEGF) Receptors] and the constant region of human IgG1.  This fusion protein was designed as an inhibitor of VEGF in blood and in the extravascular space. The efficacy of this molecule in lung cancer was investigated in a Phase 3 study.  The primary objective of the study (called VITAL) was to determine if  overall survival for aflibercept + docetaxel was superior to that of docetaxel + placebo when applied as second line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).  At least 900 subjects were to be enrolled in both arms of this study.  Top line results indicated that the study did not achieve pre-specified criteria for the primary endpoint of improvement in overall survival.  The companies stated that the addition of aflibercept to docetaxel demonstrated activity as measured by key secondary endpoints of the study: progression free survival (PFS) (HR=0.82, CI: 0.716 to 0.937) and an overall objective response rate (ORR) of 23.3% (utilizing RECIST criteria) in the aflibercept arm compared to 8.9 percent in the placebo arm.  It should be noted that PFS has been shown not to correlate very well with overall survival, and it should not be taken as an indicator of efficacy in most cases.  Aflibercept is also been tested as first- and second-line treatment in metastatic colorectal cancer and as a first line treatment in hormone-resistant, metastatic prostate cancer.

March 10, 2011

BioSante's Pancreatic Cancer Vaccine Prolongs Survival in a Phase II Study

The pancreatic GVAX vaccine by BioSante is a member of similar vaccines developed by this company for an array of cancers such as prostate, breast, pancreatic, colorectal cancers, leukemia and melanoma.  GVAX (granulocyte-macrophage colony-stimulating factor [GM-CSF] gene transduced irradiated cancer cells) offers the possibility of a "host versus cancer" immune responses possibly generated in patients receiving the vaccine.  The theory behind these vaccines that the GM-CSF expressed by the vaccined cells would induce the activation dendritic cells and antigen presentation to both the B-cell and T-cell arms.  As such, these vaccines are similar to Dendreon's Provenge which is approved by the FDA.

The study that BioSante is touting as showing that its GVAX vaccine extents survival in pancreatic cancer was a single-center, uncontrolled, non-randomized phase II study performed at the Sidney Kimmel Comprehensive cancer center.  It accessed sixty (60) patients diagnosed with stage I or II of pancreatic adenocarcinoma.  The vaccine was given in combination with chemoradiotherapy.  The median disease-free survival of patients was 17.3 months (95% CI, 14.6–22.8) with median survival of 24.8 months (95% CI, 21.2–31.6). The administration of immunotherapy was well tolerated.

Despite BioSante's positive message here about the vaccine, this open-label, non-randomized, single-center study cannot really serve an indication that the vaccine is efficacious. Such studies are not good foundations for a Phase 3 progam. Considering the extent of efficacy of the Provenge in advanced, metastatic prostate cancer, it is likely that the vaccine has similar capabilities.  Obviously, a step forward, but hardly a definitive one when one considers the high costs of these vaccines (taking Provenge as the pricing model).

February 18, 2011

Exelixis Announces  Phase 2 Data for Cabozantinib (XL184) that Show Evidence of Efficacy in Patients with Castration-Resistant Prostate Cancer

Cabozantinib (XL184) is an inhibitor of certain tyrosine kinases, notabaly MET and VEGFR2.  Mutated, overexpressing and highly active versions of these receptor tyrosine kinases contribute to angiogenesis, proliferation and metastasis of malignant cells. Partial data from an open-label, adaptive discontinuation Phase 2 study in patients diagnosed with castration-resistant prostate cancer were announced in the ASCO Genitourinary Cancers  2011 Symposium in Orlando, FL.  The study examined the effect of this drug on metastatic bone lesions that are very painful. The subjects received cabozantinib orally for 12 weeks.   In the preliminary analysis, of the 72 patients enrolled, 63 had bone scans.  Of these, 52 (85%)  showed partial or full response in metastatic bone lessions by RECIST criteria (assessement performed by independent radiologists).  Also, the majority of patients with anemia showed increases in hemoglobin during the study. The patients received cabozantinib orally for 12 weeks.  [The reason that this announcement is included here is because the information provided by the company is difficult to decode. In an adaptive discontinuation study, patients are administered the experimental treatment immediately after enrollment.  Those that respond to treatment are then randomized to either continue receiving the experimental treatment or to placebo.  The data announced probably refer to the pre-randomization assessment, but a direct statement was not included.  In any case, such studies result in the enrichment of responsive study population and their results should be interpreted with caution] Cabozantinib is being studied in a variety of other malignancies including medullary thyroid cancer, non-small cell lung cancer, gliobalstoma multiforme and others.

January 21, 2011

Plexxikon's/Genentech's  PLX4032 Meets Overall Survival and Progression-Free Endpoint for Melanoma Patients in  Phase 3 Trial Study

 PLX4032 is a B-RAF inhibitor that disrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway if the B-RAF contains the V600E mutation common in melanoma patients.  PLX4032 is being co-developed by Plexxikon and Genentech/Roche.

Plexxikon Inc. today announced positive data from an interim analysis of the BRIM3 trial, a large multi-center Phase 3 clinical study of PLX4032 (RG7204) in patients with previously untreated metastatic melanoma with the common B-RAF V600E mutation.  The BRIM3 analysis showed that the study met the pre-specified criteria for co-primary endpoints of overall survical (OS) and progression-free survival (PFS). Patients treated with PLX4032 had an improved OS compared to patients treated with dacarbazine, the current standard of care. In addition, these patients showed increased PFS. It should be noted that having OS and PFS as co-primary endpoints is very important in melanomal studies, as PFS is highly influenced in this cancer by a high spontaneous remission rate.  The safety profile was generally consistent with the previous PLX4032 studies. Based on these results, patients on the dacarbazine arm of the study will have the option to crossover to receive PLX4032. Additionally, an Expanded Access Program also will now be opened to previously untreated melanoma patients with the BRAF mutation.   Combination trials with PLX4032, as well as trials in other BRAF-mutated cancers, are also planned.

January 19, 2011

ARIAD's Ridaforolimus Prolongs Progression-Free Survival in Patients with Metastatic Soft-Tissue or Bone Sarcomas:

Ridaforolimus, co-developed by Merck and Ariad Pharmaceuticals, Inc., is is a targeted small-molecule inhibitor of the protein mTOR. mTOR, a popular target of anti-neoplastic drugs, acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival. 

The Phase 3 clinical study (named SUCCEED) is examining the effect of ridaforolimus treatment in progression-free survival (PFS) in patients with metastatic soft-tissue or bone sarcomas who demonstrated a favorable response to prior conventional chemotherapy. In this multicenter, randomized (1:1), double-blind, placebo controlled study, oral ridaforolimus ws administered at 40 mg/day (five of seven days/week)

Analysis of 552 progression events in  711 patients, performed by an independent review committee showed that the study met its primary endpoint, with a statistically significant  28% (p=0.0001)reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.72). Determination of median PFS for each arm of the trial demonstrated that ridaforolimus treatment resulted in a statistically significant 21 percent (3.1 week) improvement in median PFS (ridaforolimus, 17.7 weeks vs. placebo, 14.6 weeks). Based on the full analysis of PFS determined by the investigative sites, there also was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.69). Ridaforolimus treatment resulted in a statistically significant 52% (7.7 week) improvement in median PFS (ridaforolimus, 22.4 weeks vs. placebo, 14.7 weeks). The most common side effects observed in the study included stomatitis (e.g., mouth sores), fatigue, diarrhea and thrombocytopenia. This trial remains active, and study participants continue to be followed to gather additional data on secondary endpoints, including overall survival and the safety profile of ridaforolimus. Merck, which is developing this agent in association with ARIAD Pharmaceuticals Inc, currently plans to file for marketing approval of oral ridaforolimus in 2011. 

Ridaforolimus is being developed for a number of other challenging oncology indications.  In October 2010, we reported here interim results from a Phase 2 study in advanced endometiral cancer.

Clinical Development Headlines in 2010