Archive for the ‘Topics’ Category

FDA Approves Axitinib for Advanced Renal Cell Cancer

October 7, 2012 Leave a comment

The US Food and Drug Administration (FDA) has approved axitinib (Inlyta, Pfizer) for the treatment of advanced renal cell carcinoma (RCC) that has progressed after first-line systemic therapy.

“This is the seventh drug that has been approved for the treatment of metastatic or advanced kidney cell cancer since 2005,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA’s Center for Drug Evaluation and Research, in a statement. “Collectively, this unprecedented level of drug development within this time period has significantly altered the treatment paradigm of metastatic kidney cancer, and offers patients multiple treatment options.”

In the past 6 years, the treatment options for patients with advanced RCC have expanded with the approval of several new agents with 2 different modes of action. Drugs that target vascular endothelial growth-factor (VEGF) receptors include sorafenib (Nexavar, 2005), sunitinib (Sutent, 2006), pazopanib (Votrient, 2009), and the VEGF antibody bevacizumab (Avastin, 2009); temsirolimus (Torisel, 2007) and everolimus (Afinitor, 2009) target rapamycin (mTOR).

Axitinib is a small-molecule tyrosine kinase inhibitor that works on multiple targets, including VEGF receptors 1, 2, and 3.

As previously reported by Medscape Medical News, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously in December 2011 to recommend the approval of axitinib for the second-line treatment of patients with advanced RCC.

The approval was based on a single efficacy study, A4061032 (AXIS trial), of 723 patients with advanced RCC who had failed 1 previous therapy. AXIS was a randomized, controlled, open-label, multicenter phase 3 trial that compared axitinib with sorafenib as second-line systemic therapy. Patients were randomized to receive either axitinib 5 mg or sorafenib 400 mg, and the primary efficacy end point was progression-free survival.

The results showed that axitinib extended progression-free survival by 2 months more than sorafenib. Median progression-free survival was 6.7 months (95% confidence interval [CI], 6.3 to 8.4) for axitinib and 4.7 months (95% CI, 4.6 to 5.6) for sorafenib, with a hazard ratio of 0.67 (95% CI, 0.55 to 0.81). The objective response rate for axitinib was also superior to sorafenib (19.4% vs 9.4%).

“This is probably the most robust randomized trial, in that the comparator arm is an active and approved agent that is really contemporary treatment, not more historic treatment,” Deborah K. Armstrong, MD, from the Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News at the time of the ODAC vote. “I think the data in the US population are compelling, and I agree, having used sorafenib before, that having something with a different toxicity profile for patients who don’t tolerate sorafenib is certainly a plus.”

The adverse event profile for axitinib is similar to that of other drugs in the same class. The most common adverse events (>10% in either group) were diarrhea, hypertension, fatigue, decreased appetite, and nausea. Higher rates of gastrointestinal events, fatigue, asthenia, hypertension, hypothyroidism, and dysphonia were observed with axitinib than with sorafenib. However, axitinib had lower rates of dermatologic adverse events and anemia than sorafenib.

Nonfatal serious adverse events occurred in 34.8% of patients in the axitinib group and 32.7% in the sorafenib group. More deaths occurred with axitinib than with sorafenib group, and more deaths in the axitinib group than in the sorafenib group were associated with treatment-emergent adverse events (2.5% vs 1.1%).

According to an FDA statement, patients with hypertension should have it well controlled before taking axitinib, and the drug is contraindicated in patients with untreated brain tumors or gastrointestinal bleeding.

Categories: Topics

Changes in explanation of Nov 09 Q no. 10; answer remains the same – AA

October 2, 2012 Leave a comment

Correction in Nov 09 Q no. 10; answer remains the same, explanation is
10.     Vaginal sphincter is formed by all except:
a)      Internal urethral sphincter
b)      External urethral sphincter
c)      Pubovaginalis
d)      Bulbospongiosus


10.     Ans is ‘a’ i.e. Internal urethral sphincter  [Ref: Moore’s
Anatomy 5/e p402; Anatomy at a glance By Omar Faiz, David Burns Moffa
p61; Gray’s Anatomy 40/e p1094-1096; BDC 4/e vol. 2 p393; Practical
guide to female pelvic medicine  By Gamal M. Ghoniem, G. Willy
There is no ‘internal urethral sphincter’ in females. It is present in
males at the bladder neck and proximal urethral. Its function is to
prevent retrograde ejaculation of semen into the bladder during the
time of ejaculation.
In males the detrusor muscle fibers of the bladder at the region of
bladder neck and proximal urethra are organized into internal urethral
sphincter which is under involuntary control.
In females the musculature surrounding the internal urethral orifice
of the bladder is not organized into an internal sphincter.
External urethral sphincter is present in both males and females.

Vaginal sphincter is formed by the fibres of pubococcygeus known as
pubovaginalis. There are other muscles also which contribute in
compressing the vaginal orifice.
The Bulbospongiosus muscle fibres run anteriorly on either side of the
vagina to attach to the corpora cavernosa of the clitoris and
posteriorly to perineal body. Bulbospongiosus in females acts to
constrict the vaginal orifice and express the secretions of greater
vestibular glands.
The external urethral sphincter is composed of 3 muscles – sphincter
urethrae, compressor urethrae, and urethrovaginalis sphincter (or
muscle); last 2 muscles found in females only.
When external urethral sphincter contracts to compress the urethra, it
compresses the vaginal orifice also.

Categories: Topics

FDA Approves Regorafenib for Metastatic Colorectal Cancer

September 28, 2012 Leave a comment

The US Food and Drug Administration (FDA) has approved the oral therapy regorafenib (Stivarga, Bayer) for the treatment of metastatic colorectal cancer.

Regorafenib is a novel multikinase inhibitor that blocks multiple enzymes that promote cancer growth.

“Stivarga is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past 2 months,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, in a press statement.

In August, aflibercept (Zaltrap; sanofi-aventis) was approved by the FDA for use in combination with FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy.

Regorafenib is being approved with a boxed warning that indicates that severe and fatal liver toxicity occurred in patients treated with regorafenib during clinical studies.

In the drug’s pivotal phase 3 randomized trial, known as CORRECT, median overall survival was 6.4 months in the regorafenib group and 5.0 months in the placebo group. This 29% increase in survival was originally presented at the 2012 Gastrointestinal Cancers Symposium, as reported by Medscape Medical News.

“This is the first small-molecule kinase inhibitor with proof of efficacy in metastatic colorectal cancer,” said lead author Axel Grothey, MD, at a meeting press conference held in January. He is professor of oncology at the Mayo Clinic in Rochester, Minnesota.

Because the prespecified overall survival efficacy boundary was crossed at the second preplanned interim analysis, the study was unblinded to allow patients in the placebo group to cross over, Dr. Grothey explained.

In the CORRECT study, in addition to best standard care, 505 patients were randomized to oral regorafenib 160 mg (3 weeks on and 1 week off) and 255 were randomized to placebo.

Patients were to continue with the treatment until disease progression, death, or unacceptable toxicity.

In addition to improved overall survival, median progression-free survival was better with regorafenib than with placebo (2.0 vs 1.7 months). The estimated hazard ratio for progression-free survival was 0.493 (P < .000001).

There was also a substantial difference in disease control rate in the regorafenib and placebo groups (44% vs 15%; P < .000001).

The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%), Dr. Grothey reported.

Regorafenib was reviewed under the FDA priority review program. The designation provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists, according to the agency.

Regorafenib has been approved 1 month ahead of the product’s prescription drug user fee goal date.

Categories: Topics

FDA Approves Second Oral Drug for MS

September 14, 2012 Leave a comment

The US Food and Drug Administration (FDA) has approved a second oral agent for the treatment of relapsing forms of multiple sclerosis (MS), teriflunomide (Aubagio, Genzyme/Sanofi).

“In a clinical trial, the relapse rate for patients using Aubagio was about 30% lower than the rate for those taking a placebo,” said Russell Katz, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “Multiple sclerosis can impair movement, sensation, and thinking, so it is important to have a variety of treatment options available to patients.”

The most common side effects experienced by patients in clinical trials include diarrhea, abnormal liver tests, nausea, and hair loss, the statement notes. A boxed warning will alert prescribers to the risk for liver problems, including death, and a risk for birth defects with use of teriflunomide. “Physicians should do blood tests to check liver function before a patient starts taking Aubagio, and periodically during treatment,” the FDA statement notes.

The boxed warning points out that, based on animal studies, the drug may be teratogenic, important because many patients with MS are women of childbearing age. “For this reason, Aubagio is labeled as Pregnancy Category X, which means women of childbearing age must have a negative pregnancy test before starting the drug and use effective birth control during treatment.”

The drug will be dispensed with a patient Medication Guide, the statement adds, “that provides important instructions on its use and drug safety information.”

Aaron Miller, MD, Medical Director of the Corrinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, was a member of the steering committee involved in the development of this drug. “It’s exciting to have another oral option available for people with MS,” he told Medscape Medical News.

“This is the second oral agent, and one that carries perhaps some ease of getting patients on the drug compared to the existing oral agent, and also it appears to be a very safe agent based on 2 very large clinical trials plus a very long history of use of leflunomide, a drug for which [teriflunomide] is an active metabolite,” Dr. Miller said.

Leflunomide is used to treat rheumatoid arthritis and has a history of an estimated 2.1 million patient-years of exposure, according to a statement from Genzyme.

“We are greatly encouraged to see a new oral therapeutic option become available to people living with MS,” said Timothy Coetzee, MD, chief research officer at the National MS Society, in the Genzyme release. “With collaborative research underway around the world today, this is an extremely hopeful time for anyone who is diagnosed with MS.”


Teriflunomide is a once-daily oral immunomodulator developed as a disease-modifying therapy for MS. It reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in de novo pyrimidine synthesis for DNA replication. As a result, the drug reduces T- and B-cell proliferation and function in response to autoantigens but preserves the replication and function of cells living on their pyrimidine pool, including hematopoietic cells or memory T cells, through the so-called salvage pathway.

Approval is based on results of a program of phase 3 trials. Results of the TEriflunomide Multiple Sclerosis (TEMSO) trial, published in the New England Journal of Medicine in 2011, showed a significant reduction in annualized relapse rate and sustained accumulation of disability with both the 7- and 14-mg daily doses vs placebo.

A second phase 3 trial, TENERE, showed the agent was similar to interferon beta-1a (Rebif, Merck Serono), a standard approved treatment for MS.

A third trial, Teriflunomide Oral in people With relapsing-remitting multiplE scleRosis (TOWER), showed a significant reduction in annualized relapse rates and sustained accumulation of disability with the 14-mg dose vs placebo. A second dose studied in this trial, 7 mg, showed a reduction in relapse rate but not in sustained accumulation of disability.

In these trials, the incidence of serious adverse events was similar between teriflunomide- and placebo-treated patients, the Genzyme statement notes. The most common adverse events associated with treatment were increased alanine aminotransferase levels, alopecia, diarrhea, influenza, nausea and paresthesia.

Two other phase 3 trials are still ongoing, the TOPIC trial in early MS or clinically isolated syndrome, and TERACLES, investigating teriflunomide as an adjunct to therapy with interferon.

Genzyme also has a second candidate treatment for MS under consideration by FDA with the phase 3 program of alemtuzumab (Lemtrada). Alemtuzumab is given for 5 days intravenously, then for 3 days 1 year later, and has been shown to be superior to interferon in the CARE-MS 1 and CARE-MS 2 trials.

The company hopes teriflunomide could provide an option for first-line therapy, while alemtuzumab would provide an alternative for patients who continue to have disease activity on first-line treatment. Genzyme reported earlier this month though that they received a Refuse to File letter from the FDA on alemtuzumab, asking for revisions to the presentation of the data so regulators could “better navigate” the application.

“We have had constructive dialogue with the FDA, and we are very confident in our ability to address the agency’s request and resubmit rapidly,” noted David Meeker, president and CEO of Genzyme, in a company release at the time.

“We are very excited to introduce Aubagio as a new treatment option that can make a difference in the lives of people with multiple sclerosis,” Meeker said in the new Genzyme statement. “The approval of our first MS therapy represents an important milestone for Genzyme and underscores our commitment to long-term leadership and partnership in the MS community.”

Other Agents

Fingolimod (Gilenya, Novartis) was the first oral treatment approved in September 2010 for relapsing MS. Since then, changes have heen made to the label to reflect FDA concerns about cardiovascular effects of the drug after the first dose.

A release from Novartis on the teriflunomide approval underlines the safety record of fingolimod.

“Novartis pioneered the advent of oral MS treatments with the introduction of Gilenya (fingolimod), the only once-a-day oral disease modifying therapy (DMT) for relapsing MS with proven efficacy beyond an injectable therapy (interferon beta-1a),” the statement notes. “Gilenya is approved for first line therapy, and studies have consistently shown that it works across multiple disease activity measures.”

In postmarketing experience, the statement adds, fingolimod “has a demonstrated safety profile established in both clinical trials and real-world use in approximately 41,000 patients worldwide.”

Two other candidates for oral treatment are in late-stage investigation: BG-12 (dimethyl fumarate, Biogen Idec) has been shown in 2 phase 3 trials, DEFINE and CONFIRM, to reduce relapse rates, and has been submitted for review to the FDA and the European Medicines Agency.

Another agent, laquinimod (Teva Pharmaceuticals Inc./Active Biotech), had something of a setback when large phase 3 trials ALLEGRO and BRAVO showed somewhat divergent results; now, a third large trial, CONCERTO, will hopefully clarify effects of the drug.

Categories: Topics

FDA approves new orphan drug for chronic myelogenous leukaemia

September 5, 2012 Leave a comment

The US Food and Drug Administration on Tuesday approved Bosulif (bosutinib) to treat chronic myelogenous leukaemia (CML), a blood and bone marrow disease that usually affects older adults.

An estimated 5,430 men and women will be diagnosed with CML in 2012. Most people with CML have a genetic mutation, called the Philadelphia chromosome, which causes the bone marrow to make an enzyme called tyrosine kinase. This enzyme triggers the development of too many abnormal and unhealthy white blood cells called granulocytes. Granulocytes fight infection.

Bosulif is intended for patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies, including imatinib. Bosulif works by blocking the signal of the tyrosine kinase that promotes the development of abnormal and unhealthy granulocytes.

“With the approval of tyrosine kinase inhibitors, we are seeing improvements in the treatment of CML based on a better understanding of the molecular basis of the disease,” said Dr Richard Pazdur, director of the Office of Haematology and Oncology Products in the FDA’s Centre for Drug Evaluation and Research. “These improvements have been observed in chronic and accelerated phases of CML.”

Other drugs recently approved by FDA to treat various forms of CML include imatinib (2001), dasatinib (2006) and nilotinib (2007).

The safety and effectiveness of Bosulif was evaluated in a single clinical trial that enrolled 546 adult patients who had chronic, accelerated or blast phase CML. All patients had disease that progressed after treatment with imatinib or imatinib followed by dasatinib and/or nilotinib, or who could not tolerate the side effects of prior therapy. All patients in the trial were treated with Bosulif.

In patients with chronic phase CML, efficacy was determined by the number of patients who experienced a major cytogenetic response (MCyR) within the first 24 weeks of treatment. Results showed 34 per cent of patients who had been previously treated with imatinib achieved MCyR after 24 weeks. Of the patients who achieved MCyR at any time, 52.8 per cent had their response last at least 18 months. Among patients previously treated with imatinib followed by dasatinib and/or nilotinib, about 27 per cent achieved MCyR within the first 24 weeks of treatment. Of those who achieved MCyR at any time, 51.4 per cent had their MCyR last at least nine months.

In patients with accelerated CML previously treated with at least imatinib, 33 per cent had their blood counts that returned to normal range (complete haematologic response) and 55 per cent achieved normal blood counts with no evidence of leukaemia (overall haematologic response) within the first 48 weeks of treatment. Meanwhile, 15 per cent and 28 per cent of patients with blast phase CML achieved complete haematologic response and overall haematologic response, respectively.

The most common side effects observed in those receiving Bosulif were diarrhoea, nausea, a low level of platelets in the blood (thrombocytopenia), vomiting, abdominal pain, rash, low red blood cell count (anaemia), fever and fatigue.

Bosulif is marketed by Pfizer.

Categories: Topics

Newer Drugs Approved by FDA in 2012

August 16, 2012 Leave a comment

Vismodegib: T/t of basal cell carcinoma
Ingenol mebutate: T/t of actinic keratosis
Sklice (ivermectin) lotion; Treatment of head lice
Bio-T-Gel (testosterone gel): For the treatment of hypogonadism,
Linagliptin + Metformin: T/t of type II diabetes
Mifepristone: Control of hyperglycemia in adults with endogenous Cushing’s syndrome
Pancrelipase: T/t of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions
Taliglucerase alfa: T/t of Gaucher disease
Peginesatide: T/t of anemia due to chronic kidney disease
Beclomethasone dipropionate nasal aerosol: T/t of seasonal and perennial allergic rhinitis
Rotigotine Transdermal System: T/t of Restless Legs Syndrome
Avanafil: T/t of erectile dysfunction
Pazopanib: T/t of soft tissue sarcoma
Everolimus: T/t of renal angiomyolipoma associated with tuberous sclerosis complex
Axitinib: T/t of advanced renal cell carcinoma
Glucarpidase: T/t of toxic plasma methotrexate concentrations in patients with impaired renal function
Fentanyl sublingual spray: For the treatment of breakthrough cancer pain
Estradiol valerate/dienogest: T/t of heavy menstrual bleeding
Tafluprost ophthalmic solution:For the treatment of elevated intraocular pressure
Surfaxin (lucinactant): T/t of respiratory distress syndrome in premature infants
Kalydeco (ivacaftor); Vertex Pharmaceuticals; For the treatment of cystic fibrosis with the G551D mutation in the CFTR gene, Approved January of 2012

Categories: Topics

Monoclonal antibodies at a glance

August 16, 2012 Leave a comment

Categories: Topics
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