Oral Rivaroxaban completes Phase III

In a race to replace warfarin and smoothen management issues of thromboembolic disorders by avoiding need for stringent therapeutic monitoring, newer oral anticoagulants are making their debut in the market soon. Rivaroxaban (BAY 59-7939) along with two newly developed molecules, Apixaban and Dabigatran etexilate are oral form of anticoagulant agents with a convenient fixed once or twice daily dose regime. ¹ Compare to Warfarin, these drugs do not require coagulation monitoring as being highly specific direct inhibitor of Factor Xa (Rivaroxaban, Apixaban) and Factor IIa (aka, Direct thrombin inhibitor - Dabigatran etexilate). Dabigatran is about to launch in market with completed phase 3 trial in orthopedics and currently running trials in stroke prevention ⁴.

Phase 3 trial, RECORD3 (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE) data from 2531 patients, lead by Michael R. Lassen, MD announced today at the XXI International Society on Thrombosis and Haemostasis (ISTH) Congress showed once-daily rivaroxaban (Xarelto®) achieved superior efficacy in the prevention of venous thromboembolism (VTE) in patients undergoing knee replacement surgery in a head-to-head comparison with enoxaparin, the current standard of care therapy [49% relative risk reduction (RRR) (p<0.001)]. ² Importantly, rivaroxaban also demonstrated a similarly low rate of major bleeding compared to enoxaparin (0.6% and 0.5%, respectively). Considering potential hepatotoxiciy of direct thrombin inhibitors (i.e.: withdrawal of the direct thrombin inhibitor ximelagatran shortly after it reached the market ³), complete saftey profile of rivaroxaban is due till ongoing RECORD3 trial ends by 2007 end. To date, rivaroxaban is the most studied oral direct factor Xa inhibitor in development. More than 15,000 patients have been evaluated in the completed phase II programs and enrolled thus far in the phase III programs. More than 40,000 patients are expected to be evaluated in total. ⁴

Rivaroxaban is being jointly developed by Bayer HealthCare AG and Johnson & Johnson Pharmaceutical Research & Development (J&JPRD), L.L.C.

References:
1. Rivaroxaban Looks Promising in DVT - Medscape Heartwire
2. Phase III Trial Results Show Superiority of Rivaroxaban over Enoxaparin for the Prevention of Venous Thromboembolism in Patients Undergoing Knee Replacement Surgery - Pressnote at Bayer Inc. | ISTH 2007 website
3. AstraZeneca Decides to Withdraw Exanta™ (melagatran / ximelagatran)
4. Currently active clinical trials from ClinicalTrials.gov

• Rivaroxaban
• Dabigatran

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Oral Eltrombopag - A possible answer to Platelet Transfusions

A newer oral form of therapy is expected soon in market for patients of chronic ITP and possibly for other patients suffering from symptomatic thrombcytopenia. Eltrombopag (Promacta ® - GSK pharma) is an investigational agent (SB 497115) of a new drug class, thrombopoeitin receptor (TPO-R) agonist which in turn showed significant increase in megakaryocyte proliferation and differentiation and thereby, raising platelet count with oral dosage of 50-75 mg/day for six-weeks and producing less frequent chances of bleeding. This was concluded from phase III trials, involving 114 patients from worldwide having platelet count less than 30000/cmm. Being a non-peptide, small molecule, drug has less immunogenic potential, compare to platelet antibody issue with platelet transfusions. Till date, no serious side effects have been reported in controlled trials and drug is in phase III trial for further safety checkup. Though drug showed impressive results in chronic ITP non-responders from conventional treatments (steroids, immunotherapy), it is currently not being evaluated in other causes of thrombocytopenia, especially in drug-induced thrombocytopenic cases.







Image courtesy: 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)



References:

1. Press Release at GSK | Medical News Today 12 June 2007

2. Ongoing clinical trials:

• RAISE (RAndomized placebo controlled ITP Study with Eltrombopag)
• REPEAT (Repeat ExPosure to Eltrombopag in Adults with Idiopathic Thrombocytopenic Purpura)
• EXTEND (Eltrombopag Extended Dosing Study) and four others at clinicaltrials.gov

3. Original article presented presented at the 12th congress of the European Hematology Association (EHA) in Vienna, Austria

Bussel, J., Provan A., Shamsi T et al. Eltrombopag Raises Platelet Count and Reduces Bleeding compared with Placebo during Short-term Treatment in Chronic Idiopathic Thrombocytopenic Purpura: A Phase III Study. Presented 9th June 2007, 12th Congress of the European Hematology Association, Vienna, Austria

Related articles and Recent Study Outcomes:

• Eculizumab (Soliris) for paroxysmal nocturnal hemoglobinuria | On this blog
• Multiple Myeloma: Great Progress in the Treatment of Bone Marrow Cancer | Revlimid , Velcade - Google Search
• Improvements in Haemophilia Therapies

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Rosiglitazone update and Clinical Practice Guidelines: Type 2 DM

FDA has released ¹ MedWatch alert for Avandia (rosiglitazone) in management of DM, concerning about risk of ischemic cardiovascular events which might be linked with the drug use. Alert is based on pooled analysis of 42 clinical trials. However, there is no definite evidence so far showing Avandia as a cause of such cardiac events.



Joslin Diabetes Center (JDC) has released (Jan 2007) updated clinical practice guidelines on adult with diabetes and pharmacological management of type 2 DM in non-pregnant adults. These evidence based guidelines contain essential points in managing diabetic patients with a systematic approach for an optimal blood glucose control and preventing diabetic complications. Guidelines are available in text layout at NGC and also in easy-to-follow algorithms at JDC's website ².



References:

1. FDA MedWatch: 21 May 2007 Avandia (rosiglitazone)

2. Guidelines may show update after actual posting date:

• Clinical guideline for adults with diabetes: NGC | JDC (PDF)
  
  
• Clinical guideline for pharmacological management of type 2 diabetes: NGC | JDC (PDF)
  
  

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oropharyngeal cancer and oral sex

Security is mostly a superstition. It does not exist in nature,....
(Helen Keller)

The quote seems true even in a personal life! Oropharyngeal cancer showed strong association with high-risk sexual behaviors, people having more than 5 oral-sex partners during lifetime and especially among partners having HPV-16 and other serotypes positive status, results recently published in NEJM. A Case-control study involving newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer.

The degree of association increased with the number of vaginal-sex and oral-sex partners. Since this is a single study with fairly ok sample size, cause-and-effect association can not be established; but there is a strong correlation between oropharyngeal cancer and oral HPV infection, apart from use of alcohol and tobacco as an independent risk factors. Apart from oro-genital sex, even mouth-to-mouth direct contact may be linked to increase risk of acquiring oral HPV infection and subsequently oropharyngeal cancer.

Authors suggest public health implication of this study by expecting rise in oropharyngeal cancer cases because of increase oral sex practices behavior among adoloscents. Recently launched HPV vaccine (Gardasil, Merck Inc.), now under US national immunization schedule for girls between 11 to 12 years (extended 9-26 years age) can be a rational approach to prevent oral HPV infection and decreasing cancer risk in boys too. However, more clinical studies are demanded before arriving at conclusion to implement HPV vaccination among boys.

Reference:
1. D'Souza G et al. | Case–Control Study of Human Papillomavirus and Oropharyngeal Cancer | N Engl J Med 2007(10 May);356:1944-1956 (free access)
2. Oral Sex Can Add to HPV Cancer Risk | Time magazine
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Helen Keller says to dare and face the outright danger. However, there are few exceptions prudent followers should know about. Play safe:-)

Cumulative Updates: Stroke Guideline | New Anti-Platelet drug in Phase 3

Here are cumulative updates (shortlist) happened in recent two weeks. I am unable to post frequent regular updates because of tight schedule and limited internet connectivity. Alternately, use feed station for keeping eye on medical news.

1. Updated guidelines for treatment of acute ischemic stroke:
By American Heart Association/American Stroke Association (Apr 19, 2007, ahead of print issue of Stroke)

Major Recommendations/Changes since 2003 guidelines

• Intravenous tPA is still recommended as the key treatment of stroke in patients presenting within 3 hours of the onset of stroke symptoms
• Time is the key, activation of emergency medical services ASAP is the topmost priority
• Upcoming role of intra-arterial tPA in patients with inaccessible intravenous line
• Comaprision of benefits Vs risks using Mechanical Embolus Removal in Cerebral Embolism (MERCI) retriever (FDA approved) or tPA.
• CT scan still remains preferred modality with only primary intetion to exclude hemorrhage event and plan for tPA treatment
• MRI is acceptable alternative provided quick access is available

..... guidelines truncated

Refer Medscape article (link) or Stoke journal (May 2007 issue) for complete guidelines.

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2. Newer Anti-platelet drug in Phase 3 clinical trial:
Newer class of oral anti-platelet drug (platelet PAR-1 receptor blocker) named TRA-SCH 530348 (Schering-Plough Inc.). In fact, it blocks the platelet PAR-1 receptor to which thrombin binds, thus inhibiting thrombin-induced activation of platelets, and is therefore classified as a thrombin-receptor antagonist (TRA). Recently reported phase 2 trial showed fewer ischemic events without increasing bleeding when added to standard antiplatelet therapy with aspirin and clopidogrel in patients undergoing PCI. Researchers from Duke and TIMI group have now planned two major phase 3 trials which will be accessing effect of this novel agent compare to placebo without adjuvant standard anti-platelet regime. Two groups of patients will include one for the treatment of acute coronary syndrome (ACS) patients (more than 10000 patients), and one for secondary-prevention in patients who have had a prior MI or stroke or who have existing peripheral arterial disease.
.....update truncated

Original press release at http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=987054
Courtesy: Medscape

SBAmin.com is down: Server Shifting In Progress

Copy of original post:

Site Status: DOWN | Blog Status: Healthy

Dear Visitor,

Because of an ongoing data corruption error, we are shifting site servers to new, stable ones. Henceforth, SBAmin.com may not be available for next 24-48 hours. However, Blog Junction (status: Healthy) is active throughout site maintenance period.
Also, please note change in email contact information. Kindly do not email me at Instead use this link OR email me at till further update.

I'll be updating here soon as site status becomes OK.

Sorry for inconvenience!

Regards,
Samir
21 April 2007 1227 +0530
Baroda India
T: (0091) 93762 26975
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Declining Breast Cancer & HRT effect

Hormone Replacement Therapy (HRT) is again in the news, once again with possible causal association for developing breast cancer. Statistical analysis performed by M.D.Anderson's team revealed strong association (but no cause-to-effect relationship) between declining breast cancer cases and parallel decline in use of HRT in post-menopausal women since mid-2002. The decline occurred primarily in women age 50-69, the researchers find, and was predominantly seen in estrogen-receptor(ER)-positive cancer. Ravdin and Berry strongly stress, however, that their study is not suggesting that all women stop their use of HRT. "This study is not saying that an individual woman will reduce her absolute risk of developing breast cancer by 15 percent by immediately discontinuing use of HRT," Berry says.

Read brief report at EurekAlert! 18 Apr 2007
Original article: Ravdin PM et al. | The Decrease in Breast-Cancer Incidence in 2003 in the United States | N Engl J Med 2007(Apr 19);356:1670-1674

Inhaled Insulin (Exubera) - Falling Star

Inhaled Insulin (Exubera) was brought in market in early-2006 and since then, it's being criticized for its added efficacy and long-term safety profile over standard subcutaneous insulin regime. Recently, National Institute for Health and Clinical Excellence (NICE, UK Government) has published guideline on use of inhaled insulin for the treatment of type 1 and 2 diabetes. Authors of guideline group do not recommend inhaled insulin for the routine treatment of diabetes.

Also, inhaled insulin should be used as an alternative option in only those subgroup of diabetic patients in whom other treatment modalities are ineffective or intolerable and interestingly, in patients suffering from specific phobia of "blood injection injury type" who are not willing to take standard subcutaneous insulin injections. Several other studies also recommend data collection for evaluating long-term safety profile of inhaled insulin and it's effect on lung functions.

Reference:
1. NICE guideline (Dec 2006): Inhaled insulin for the treatment of diabetes (types 1 and 2)
2. Exubera | Pfizer Inc.
3. FDA approval of Exubera
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