Thieme Publishing Group is pleased to announce the launch of Pharmaceutical Substances Version 3.2. Available via Thieme-connect, Pharmaceutical Substances is a comprehensive reference guide to every significant pharmaceutical compound and includes all FDA approved active pharmaceutical ingredients (APIs).

Fifteen drugs have been added to the upgraded version of the information resource, bringing the total of APIs to 2,475. Recent additions include Novartis’ new anti Malaria drug Riamet, the Japan-only available anti-psychotic drug, Lonasen from Sumitomo Pharma and Evoltra, Bioenvision’s new Leukemia treatment. And the monograph for Dexrazoxane has been updated with new synthetic routes.

“We strive to keep Pharmaceutical Substances as current as possible. With this update, important drugs that were approved in the last two years, but not yet covered in the product, have been added,” says Dr. Thomas Krimmer, who is in charge of Pharmaceutical Substances at Thieme. “The update is available from mid-May for the users of Thieme’s structure- and full text searchable stand-alone electronic version and from the end of this month for the users of the STN version.”

Compiled by leaders in the field of pharmaceutical chemistry, in association with InfoChem and FIZ Chemie, the online version of the information resource is an easy-to-navigate, web-based portal that utilizes standard browser technology. The user-friendly interface enables users to rapidly locate data and graphically search structures.

Source
Thieme

Results and updates from eight studies were presented during a late-breaking trials session at Heart Failure 2009. Reviewing them at a press conference, Professor John McMurray, President of the Heart Failure Association, described the trials’ objectives and main implications.

A multicentre study of a new inotropic drug (which increases the contraction and pumping of the heart), CK-1827452, found that it increases systolic function in stable heart failure patients - and was well tolerated in a proof of concept study. CK-1827452 is a new drug in a class known as Selective Cardiac Myosin Activators. Bigger trials are now needed to assess safety and effect on clinically meaningful endpoints.

Pre-RELAX-AHF is another proof of concept study with an interesting new vasodilator drug (relaxin), a hormone produced by the ovaries and placenta during pregnancy which causes expansion of the cervix and uterus. Because relaxin also relaxes arteries and veins, it reduces the resistance to bloodflow in these vessels - and hence the work the heart has to do to pump blood through them. Results of this trial are encouraging and showed that relaxin given for 48 hours produce rapid and sustained improvement in breathlessness and other heart failure symptoms, with a favourable impact on clinical outcomes at 60 days. Again, bigger trials are now needed to assess safety and effect on clinically meaningful endpoints.

CHANCE (Congestive Heart failure: A multidisciplinary Non-pharmacological approach for Changing in rE-hospitalisation and prognosis) is an important study from Russia looking at whether post-discharge non-pharmacological interventions by nurses and other health professionals could reduce the risk of hospital readmission. The study found that an approach of patient education and active follow-up (added to optimal medical care) decreased morbidity and mortality. This reinforces the findings of previous studies in other countries and suggests that organised multidisciplinary care is beneficial for patients with heart failure in a variety of healthcare systems.

B-convinced is a multicentre French study designed to assess the effect of temporarily discontinuing beta-blockers in patients whose worsening heart failure leads to hospital admission. This reflects a frequent clinical dilemma - but results showed that during acute heart failure beta-blocker therapy should not be withdrawn.

CHAT (Chronic Heart failure Assistance by Telephone) is a fascinating study looking at whether telephone intervention (with advice about symptoms, treatment, etc) might be helpful in reducing the risk of major heart failure events (hospital admissions/death) in patients living in rural areas (where organised multidisciplinary care is not available). Results from this randomised trial - performed in Australia - suggest that telephone support can significantly reduce mortality and hospitalisation rate in a rural and remote cohort.

CIBIS-ELD (Cardiac Insufficiency Bisoprolol Study in Elderly) was designed to assess and compare the dose of two proven beta-blockers in elderly patients with heart failure (the elderly are often “underdosed” and there is always debate about whether one drug might be better tolerated than another). This study showed that it is indeed hard to achieve the target dose in elder patients, and that there was no difference in tolerability between the two (bisoprolol and carvedilol).

Ex-DHF is an interesting study which looked at a neglected type of heart failure, diastolic HF (or HF with preserved ejection fraction). There are no proven treatments for this type of heart failure, and this study tested the value of exercise training. The results showed that this intervention improved exercise capacity, made patients feel better and, importantly, seemed to improve the abnormalities in the structure and function of the heart in these patients.

SIGNAL-HF studied the very topical and important question of whether use of the biomarker NT-pro BNP as a guide to pharmacological treatment in primary care would lead to an improvement in patient outcomes. It didn’t - and this will be a controversial conclusion alongside a number of conflicting and unconvincing recent findings in this area.

Late-breaking trials session, 1st June, 11.00-12.30.

Heart Failure Congress 2009 is organised by the European Society of Cardiology and Heart Failure Association of the ESC, and takes place from 30 May to 2 June at the Palais Acropolis, Nice, France.

* Information on the scientific programme for Heart Failure Congress 2009 is available at http://spo.escardio.org/Welcome.aspx?eevtid=31

Source:
ESC Press Office

European Society of Cardiology

Plexxikon Inc. today announced preliminary data from a Phase 1 clinical study investigating PLX4032 (R7204). PLX4032 is a novel, oral and highly selective drug that targets the BRAFV600E cancer-causing mutation that occurs in most melanomas and about eight percent of all solid tumors. In patients whose cancer harbors this mutation and who were treated with therapeutic doses of PLX4032, tumor shrinkage and extended progression-free survival have been observed. Currently, two extension studies are being conducted in mutation-positive melanoma and colorectal cancer patients. Following the initial positive findings announced today, larger clinical trials to support a registration program for product approval are targeted to start later in 2009. Plexxikon and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.

“PLX4032 has shown both tumor shrinkage and delay in tumor progression in patients whose tumors harbor a BRAF mutation as well as reports of clinical symptom improvement in some patients,” stated Keith T. Flaherty, M.D., assistant professor at the Abramson Cancer Center of the University of Pennsylvania and principal investigator for the PLX4032 Phase 1 clinical trial. “Seven years after BRAF mutations were first identified, we have validation that this mutation is a cancer driver and therapeutic target. This is a new and important chapter in the story of targeted therapy development in cancer, and we are especially excited for our melanoma patients, for whom there are currently few treatment options.” Link to video clip of Dr. Flaherty

In the dose escalation phase of the study, 55 cancer patients have been treated, including 24 mutation-positive melanoma patients and 3 mutation-positive thyroid patients, as well as 28 melanoma, rectal and ovarian cancer patients who did not have the mutation or whose mutation status was not known.

In 16 BRAF mutation-positive melanoma patients treated with PLX4032 doses at or above 240 mg twice daily (BID), representing targeted drug exposure levels, data show:

- PLX4032 is well tolerated at very high doses, with 960 mg BID under evaluation as the maximum tolerated dose

- Partial responses in 9 patients showing greater than 30% tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with 7 confirmed

- Regression of metastatic lesions in every site to which melanoma commonly spreads, including liver, lung and bone

- Minor responses in 4 patients showing tumor regression greater than 10% but less than 30%

- Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment

- Interim median progression-free survival of at least six months, with many responding patients still receiving treatment

By contrast, no treatment response was observed in a small group of patients without the mutation, and progression-free survival was less than 2 months, consistent with historical data.

Dose-limiting toxicities, primarily rash, fatigue and joint pains, were seen at 1120 mg BID. Drug-related adverse events have been predominantly mild in severity and transient, including rash and photosensitivity. Serious adverse events were observed in some patients after chronic treatment, including possibly drug-related cutaneous squamous cell carcinoma. A risk management plan has been implemented for baseline evaluation of the skin and monitoring of all patients while on study. Cutaneous squamous cell carcinoma is typically excised by a patient’s dermatologist.

“This is a significant day for us at Plexxikon. The clinical data for PLX4032 so far support our hypothesis that a truly selective drug can target tumors harboring this cancer-causing mutation, while at the same time, deliver a treatment that is well tolerated by patients,” stated K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “In conjunction with bio-response markers and a companion diagnostic test, PLX4032 has all the hallmarks of an ideal personalized medicine. Plexxikon’s pipeline includes several highly selective kinase inhibitors, including novel therapies for other cancers as well as other chronic diseases such as rheumatoid arthritis where such precision is anticipated to provide a safety advantage.”

Companion Diagnostic in Parallel Development

Along with the development of PLX4032 therapy, a diagnostic test to identify patients with the BRAF mutation is being co-developed by Plexxikon and Roche, under a separate 2005 agreement. This test is already being used to identify mutation-positive patients for ongoing clinical trials. Most importantly, this companion diagnostic enables the identification of mutation-positive cancer patients considered most likely to respond to PLX4032 treatment.

Exploring PLX4032 in Colorectal and Other Cancers

The prevalence of the BRAF mutation is about eight percent of all solid tumors. Preclinical studies in colorectal cancer models also suggest that PLX4032 causes tumor regression, either as a single agent or in combination. Hence, future clinical trials may evaluate PLX4032 in tumor types beyond melanoma.

Currently, one of two extension cohorts is recruiting mutation-positive colorectal cancer patients in order to evaluate PLX4032 in this target population. In a retrospective study of 600 patients with colorectal cancer, including all stages and both genders, tumor tissue was tested for the presence of the BRAF mutation and correlated with outcomes. The data confirmed that approximately 10 percent of colorectal cancer patients carry this mutation, which is independent of the KRAS mutation, and those BRAF mutation-positive patients have a much poorer prognosis than patients with wild-type BRAF (ASCO 2009 Abstract #1103).

Additionally, in the Phase 1 dose escalation study which enrolled patients with several different tumor types, one mutation-positive thyroid patient showed a confirmed partial response, while two others showed stable disease with prolonged therapy.

Biomarkers Enhance Development of Personalized Medicine

The development of PLX4032 has employed a variety of translational tools, including bio-response markers and an in vitro diagnostic test. These tools can potentially enable early detection of targeted pathway modulation and treatment response, as well as identification of the targeted patient population for this treatment.

Biomarker data from patient tumor biopsies before and after PLX4032 treatment showed early target modulation and when dosed at higher levels, have shown nearly complete inhibition of the desired target (ASCO 2009 Abstract #9021).

About PLX4032 (R7204)-A Personalized Medicine for Cancer Treatment

PLX4032 is a novel, oral small molecule for the treatment of melanoma and other cancers harboring the V600E mutation of the BRAF kinase gene. This defect is present in approximately 60 percent of melanoma skin cancers, and occurs in about eight percent of all solid tumors, including melanoma, colorectal, thyroid and other cancers. Preclinical data suggest that Plexxikon’s novel anti-cancer compound selectively targets and inhibits tumor cells which contain this cancer-causing mutation. In contrast to many other kinase inhibitors available, PLX4032 is highly selective for its primary target, and does not have significant activity on other kinase targets.

About Melanoma

Melanoma is the most serious type of skin cancer. More than 50,000 people in the U.S. are diagnosed with melanoma each year, but the percentage of people in the U.S. who develop melanoma has more than doubled in the past 30 years. Worldwide, about 160,000 new cases of melanoma are diagnosed annually. Melanoma is treatable if caught early but is very deadly when it becomes metastatic. The median progression-free survival for a patient with metastatic melanoma is less than 60 days, and the median overall survival for these patients is less than 12 months. Patients who develop metastatic disease are rarely cured with available treatments.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients.

In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: http://www.roche.com.

Source
Plexxikon