Actelion Ltd (SIX: ATLN) announced that the Independent Data and Safety Monitoring Board (DSMB) has recommended continuation of the pivotal Phase III study BUILD-3, evaluating the efficacy and safety of bosentan (Tracleer®) in patients suffering from idiopathic pulmonary fibrosis.

The DSMB was mandated to perform an efficacy and futility interim analysis of 75% of events in BUILD-3 to assess whether study continuation is warranted based on the primary objective of demonstrating delayed disease worsening or death.

Final study results are expected before the end of 2009.

About Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a progressive and usually fatal disease of the lung interstitium. It is estimated that there are around 60,000 patients worldwide with a confirmed diagnosis of idiopathic pulmonary fibrosis (IPF).

In IPF, patients experience progressive dyspnea due to loss of lung function and scarring of the lung. As tissue becomes thicker it causes an irreversible loss of the tissue’s ability to transfer oxygen into the bloodstream. Endothelin-1 besides its potent vasoconstriction properties has direct pro-fibrotic and pro-inflammatory effects. Since endothelin concentrations are elevated in interstitial lung disease, there is also evidence implicating endothelin in this disease.

For patients with IPF outside Japan, there are currently no approved therapies available.

About BUILD-3

BUILD-3 (Bosentan Use in Interstitial Lung Disease) is a multicenter, double-blind, randomized, placebo-controlled, parallel group, event-driven morbidity/mortality study evaluating the safety and efficacy of bosentan 125mg bid in IPF patients. BUILD-3 enrollment was completed in November 2008 with 616 patients.

The study is randomized with two bosentan patients to one placebo patient and is planned to reach 202 events. Following the second interim analysis (75% of events) by an independent Data and Safety Monitoring Board, the study continues as planned. BUILD-3 is conducted under a Standard Protocol Assessment (SPA) with the US FDA.

About BUILD-1

In November of 2005, Actelion reported the results of BUILD-1, a clinical study in idiopathic pulmonary fibrosis. Although not statistically significant for the primary end-point, positive trends for predefined secondary end-points were observed such as the combined incidence of disease progression or death at 12 months (36.1% in the placebo group versus 22.5% in the bosentan group), representing a relative risk reduction of 38% (95% CI, -5 to 63%; p=0,078). [5]

About Tracleer® in Pulmonary Arterial Hypertension (PAH)

Tracleer® (bosentan), the first oral dual endothelin receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH) and made available by Actelion subsidiaries in the United States, the European Union, Japan, Australia, Canada, Switzerland and other markets worldwide.

About Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected individual. The function of the heart and lungs is severely compromised, manifested by a limited exercise capacity, and, ultimately, a reduced life expectancy. Approximately 100,000 people in Europe and the United States are afflicted with either primary or secondary forms of the disease related to conditions or tissue disorders that affect the lungs, such as scleroderma, lupus, HIV/AIDS or congenital heart disease.

PAH is associated with structural changes in both the pulmonary vasculature and the right ventricle. Recent advances [2] in the understanding of the pathogenic factors leading to the pulmonary vascular disease have led to the development of new therapies targeting specific pathways (the prostacyclin pathway; the endothelin pathway; and the nitric oxide pathway) [3]. The available therapies have positive effects in PAH, but they do not provide a cure, and in many patients the disease will progress. PAH remains a serious life-threatening condition [3,4]. Early recognition and an understanding of the selection and timing of therapeutic options remain critical elements in the optimal management of patients with this disorder.

About Tracleer® in Digital Ulcers (DU)

DUs are a manifestation of the underlying vasculopathy which is central to the pathophysiology of systemic sclerosis (SSc) and pivotal in the development of PAH in SSc, one of the leading causes of death in SSc. Endothelin, a pathogenic mediator, is implicated in the underlying vasculopathy in SSc.

DUs can be a frequent, persistent and debilitating complication of SSc. They are caused by a reduction in the lumen of small bloody vessels that decreases blood flow to the fingers and toes causing open sores. DUs are painful, with a debilitating impact on patients’ daily life, often making it impossible to work and undertake even simple day-to-day activities, particularly those associated with fingertip function. Reducing the occurrence of new DUs is an important and achievable treatment goal in SSc.

In the EU, Tracleer® is indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Tracleer® has been shown to improve hand function (i.e. dressing and hygiene) in patients with scleroderma-induced digital ulcers.

Requires attention to two significant safety concerns [1]: Potential for serious liver injury (including rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring) - Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter. High potential for major birth defects - Pregnancy must be excluded and prevented by two forms of birth control; monthly pregnancy tests should be obtained. Because of these risks, Tracleer® is only supplied through controlled distribution.

References

1. Tracleer® SPC

2. Farber HW; Loscalzo J. Mechanisms of disease: pulmonary arterial hypertension. N. Eng. J. Med. 2004; 351:1655-65.

3. Humbert M; Sitbon O; Simonneau G. Treatment of pulmonary arterial hypertension. N. Eng. J. Med. 2004;351:1425-36.

4. Humbert M; Morrell NW; Archer SL; et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2004; 43: Suppl. 12: 13S-24S.

5. King T.E. et al. High-resolution computed tomography (HRCT) features correlate with response to bosentan in idiopathic pulmonary fibrosis (IPF): the BUILD 1 study [abstract]. Am J Respir Crit Care Med. 175:A567; 2007.

Source
Actelion Ltd

View drug information on Tracleer.

Numerous Methods Available for Dose Escalation in Phase I Trials

Numerous methods are available for dose escalation in phase I clinical trials, but most trialists continue to use traditional designs, according to a review by Lillian L. Siu, M.D., of the University of Toronto, and colleagues.

The authors describe traditional rule-based designs, as well as newer methods, including model-based designs that aim to more rapidly predict toxic doses. They also discuss trial methods for the assessment of molecularly targeted drugs that rely on biological endpoints rather than toxicity endpoints. Advantages and disadvantages of each of these designs are elucidated, as well.

By searching the literature for phase I trials published in 2007 or 2008, the authors found that the vast majority of phase I studies still use traditional rule-based designs.

“Deriving the optimal (ie, efficient and safe) dose escalation methods for anticancer therapies continues to be a chal¬lenge. However, there are many new designs proposed in recent literature. The use and evaluation of these new methods should be encouraged so that further improvements can be made to expedite the drug development process,” the authors conclude.

Lymphovascular Invasion Is Not an Independent Risk Factor for Breast Cancer Recurrence

Lymphovascular invasion was associated with poorer outcomes in patients already classified as having high risk breast cancer, but not in patients classified as having low-risk disease.

Prior studies have suggested that lymphovascular invasion by tumor cells was associated with poorer outcome. It has not been clear, however, whether lymphovascular invasion was sufficient reason to upstage a patient from a low-risk category to a high-risk category in the absence of other high-risk disease features.

In the current study, Bent Ejlertsen, M.D., Ph.D., of the Copenhagen University Hospital in Denmark, and colleagues examined the association between lymphovascular invasion and patient outcomes in more than 15,000 women diagnosed with breast cancer between 1996 and 2002 and included in the Danish Breast Cancer Cooperative Group registry.

Lymphovascular invasion was associated with a greater than two-fold increased risk of disease recurrence and nearly a 2.5-fold increased risk of death in women who were classified by other methods as having high risk of disease. It was not associated with a difference in outcomes for patients classified by other methods as having low-risk disease.

“Based on a cohort of more than 15,000 breast cancer patients, our results do not support that lymphovascular invasion has suf¬ficient independent prognostic influence to move patients from a low-risk group to a high-risk group,” the authors conclude.

In an accompanying editorial, Nancy E. Davidson, M.D., of the University of Pittsburgh Medical School, and colleagues note that the newly reported data are in conflict with previous reports supporting the association between lymphovascular invasion and poorer patient outcomes. “…[T]he study gave the unexpected and somewhat disappointing result that lymphovascular invasion was associated with adverse outcome in patients who are at high risk for recurrence by other recognized prognostic factors, but not in those who are low risk by the same criteria,” the editorialists write. “It is therefore apparently not useful as a means to subdivide the low risk group, the group in which many clinicians and patients would like assistance.”

Immunohistochemistry Tests Distinguish Breast Cancer Subtypes

A panel of four immunohistochemistry tests can distinguish luminal A and B breast cancer subtypes.

No simple immunohistochemical test has been available to distinguish luminal A from B, which are the most common of five breast cancer subtypes defined by gene expression profiling. Luminal B is characterized by more proliferating cells and worse patient prognoses.

In the current study, Torsten O. Nielsen, M.D., Ph.D., of the University of British Columbia in Vancouver, and colleagues subtyped 357 breast tumors by gene expression profiling and tested them for Ki67 expression by immunohistochemistry to determine a cut point that distinguished between luminal A and B tumors. They then examined 2,847 independent breast tumors with four immunohistochemical tests, including estrogen and progesterone receptor expression, Ki67 expression, and HER2 status.

The researchers found that Ki67 was expressed in 13 percent or less of the cells in luminal A tumors. Using that cut point for Ki67 expression, the four immunohistochemistry tests could distinguish between luminal A and luminal B subtypes in the independent series of breast cancers.

“Although we consider breast cancer molecular subtyping by gene expression profiling to be the gold standard, we nevertheless believe that there is an immediate need for well-defined and validated immunopanels for worldwide clinical diagnostic use,” the authors conclude.

Formaldehyde Exposure Associated with Risk of Blood and Lymph System Malignancies

Individuals exposed to relatively higher amounts of formaldehyde had a higher rate of death due to blood and lymph system malignancies than those exposed to lower levels of formaldehyde in a large cohort study.

In the National Cancer Institute’s formaldehyde cohort, which was previously followed through 1994, formaldehyde exposure was associated with an increased risk of leukemia. In the current study, Laura Beane Freeman, Ph.D., of the NCI in Rockville, Md., and colleagues, extended the follow-up through 2004. The cohort includes 25,619 individuals exposed to formaldehyde at work.

With a median follow-up of 42 years, the investigators observed a positive association between all lymphohematopoietic malignancies and peak formaldehyde exposure, with a 1.37-fold higher risk among those with the highest peak exposures compared with those with the lowest level of peak exposures. There was no statistically significant association with cumulative exposure or average intensity of exposure. An excess risk was seen for several sub-types of these malignancies, most notably myeloid leukemia, with a 1.78-fold higher risk. Myeloid leukemia is the type most often associated with chemical exposures. The level of increased risk was highest earlier in the follow-up period and then declined steadily over time such that the cumulative excess risk no longer reached statistical significance.

“In the current follow-up, the overall risk of myeloid leukemia has declined from our previous report, but remains somewhat elevated. While that time trend may suggest that the previous excess risk estimates were due to chance, the pattern is consistent with a possible causal association, with the largest risks occurring closer in time to relevant exposure,” the authors write. “It is our opinion that the overall pattern of risks seen in this extended follow-up of formaldehyde workers, while not definitive, warrants continued concern.”

Disruption of PPAR-d Gene Protects Mice Against Colon Tumors

Mice deficient for the peroxisome proliferator-activated receptor-d (PPAR-d) gene developed statistically significantly fewer colon tumors in response to azoxymethane exposure than did mice carrying intact PPAR-d genes.

PPAR-d is overexpressed in human colon tumors and experimentally-induced rodent tumors, but its role in colon cancer development was unclear.

In the current study, Imad Shureiqi, M.D., of the University of Texas MD Anderson Cancer Center in Houston, and colleagues targeted disruption of PPAR-d to the intestine in mice and then tested the rate of large intestine (colon) tumor formation in response to azoxymethane exposure.

Mice with colons lacking PPAR-d developed 98.5 percent fewer tumors compared with wild-type mice. Additionally, vascular endothelial growth factor expression was suppressed in the mice lacking PPAR-d.

“These findings indicate that PPAR-d has a crucial role in promoting colonic tumorigenesis,” the authors write. “Our current demonstration of the substantial involvement of PPAR-d in colonic tumorigenesis should stimulate future efforts to test PPAR-d inhibitors for the treatment and prevention of colon cancer and should serve to caution against clinical testing of PPAR-d agonists without a complete preclinical evaluation of their possible capacity to promote tumorigenesis.”

Source:
Steve Graff

Journal of the National Cancer Institute

Intrexon Corporation announces that it has initiated treatment of the first patient in its Phase 1b clinical trial of INcell-1001/AD-1001 in patients with Stage III/IV melanoma. INcell-1001/AD-1001 is Intrexon’s most advanced immunomodulatory therapy. INcell-1001 is intended to control and enhance the immune-modulating performance of dendritic cells to treat solid tumor cancers. The trial is an open-label, dose-escalation study evaluating the safety, tolerance, transgene function, pharmacokinetics and immunological effects of intratumoral injection of transduced dendritic cells (INcell-1001). INcell-1001 has been engineered for inducible expression of human Interleukin 12 (hIL-12) using regimented dosing of an orally administered small molecule (AD-1001).

The primary endpoints of the Phase 1b study are the safety and tolerability of INcell-1001 induced by escalating doses of the activator AD-1001. Secondary endpoints include the pharmacodynamics of the AD-1001/INcell-1001 combination, as represented by hIL-12 expression levels, plus anti-tumor activity, as represented by cellular immune responses within the target tumor, draining lymph nodes and peripheral circulation.

Further information regarding this Phase 1b study can be obtained using the search identifier NCT00815607 at the NIH clinical trials website: http://www.clinicaltrials.gov.

Therapeutic Strategy

The INcell-1001/AD-1001 combination represents a first-in-class therapeutic strategy that utilizes Intrexon’s RheoSwitch Therapeutic System™ to control the in situ timing and level of cytokine expression subsequent to the intratumoral injection of reprogrammed autologous dendritic cells. Preclinical studies by Intrexon and its collaborators support the prospective importance of in situ induction when compared to historical methods utilizing constitutive (”always on”) expression of known anti-tumor cytokines.

About the Phase 1A Study

AD-1001 is Intrexon’s lead activator ligand designed to tightly control the RheoSwitch Therapeutic System™ and its regulated expression domain. AD-1001 was the subject of a previous Phase 1A randomized, double-blinded, placebo-controlled, dose-escalation, safety study in 65 normal healthy male and female volunteers. Results demonstrated that AD-1001 was well tolerated at all dose levels studied, achieved steady-state pharmacokinetics, attained high serum bioavailability levels, and yielded a metabolic half-life consistent with once-a-day dosing.

About Intrexon

Intrexon Corporation is a privately held life sciences company whose Therapeutics Division is focused on the research and development of biotherapeutic control systems to reduce toxicity while enhancing clinical outcomes. The company’s technology employs special genetic components and activator ligands to tightly control the delivery, targeting, activation, regulation and location of biologics. The company is headquartered at the Virginia Tech Corporate Research Center in Blacksburg, Virginia, with additional R&D operations in Valley Forge, Pennsylvania. More information is available at http://www.DNA.com.

Source
Intrexon Corporation