Gardasil is now an approved vaccine for the prevention of anal cancer caused by HPV types 16 and 18

Gardasil is now an approved vaccine for the prevention of anal cancer caused by HPV types 16 and 18. In addition, it is also approved to prevent anal intraepithelial neoplasia grade 1, 2 and 3 caused by HPV types 6, 11, 16, and 18.

Note:  This makes me wonder whether Cervarix which is a human papillomavirus bivalent (types 16 and 18) marketed by GlaxoSmithKline will be studied the above indication.  Cervarix is indicated for use in females age 10 through 25 to prevent cervical cancer, cervical intraepithelial neoplasia grade 2 or worse and adenocarcinoma in situ, and cervical intraepithelial neoplasia grade 1 caused by HPV types 16 and 18. 

Gardasil is approved for the above indication based on data in a randomized, controlled trial in men who identified themselves as having sex with men.  The result showed that Gardasil was able to demonstrate a 78% effectiveness in preventing  anal intraepithelial neoplasia associated with HPV-16 and HPV-18.  According to the FDA, anal cancer is the same in both female and male.  The data can be extrapolated in female population.  Hence, the new indication is applicable to both female and male. 

Gardasil is a human papillomavirus quadrivalent vaccine.  It was originally approved in 2006.  Up until now, it's been indicated for the following conditions:

• It can be used in girls and women 9 through 26 years of age to prevent
• cervical, vulvar, and vaginal cancer caused by HPV types 26 and 28
• Genital warts caused by HPV types 6 and 11

• It can also be used as vaccine to prevent certain precancerous or dysplastic lesion caused by HPV types 6, 11, 16, and 18 indicated as followed:

• Cervical intraepithelial neoplasia grade 2/3 and Cervical adenocarcinoma
• Cervical intraepithelial neoplasia grade 1
• Vulvar intraepithelial neoplasia grade 2 and 3
• Vaginal intraepithelia neoplasia grade 2 and 3
• It can also be used in boys and men age from 9 through 26 to prevent genital warts caused by HPV types 6 and 11.

Gardasil is marketed by Merck Sharp and Dohme Corp.

Dosing and Administration

• Gardasil is administered as intramuscular injection. 
• It needs to be administered in a series of 3 doses: 0, 2 and 6 months.

Adverse Reaction

• Most common adverse events: fainting, pain at the injection site, headache, nausea and fever.   
• Due to possible syncope, patients need to be seated up for up to 15 minutes after vaccinaion.

A new oral contraceptive of Watson has been approved!

Sometimes I do wonder how many different types of contraceptive pills we really need.  But I guess the need must have been ample!  (Just a side note:  Watson has over 30 contraceptive products currently on the market!  If you include other companies' products, the number can be easily over 100!)

The US FDA has just approved a "novel oral contraceptive" tablet.  The approved product consists of two types of pills:

• The first one: a combination product of 0.8 mg of norethindrone and 0.025 mg of ethinyl estradiol in chewable form. (This combination comprises of 24 pills in the kit)
• The second one which consists of 4 pills is 75 mg ferrous sulfate.  In these tablets, no hormonal active ingredient is found.

Currently, Warner Chilcott is marketing Loestrin 24 Fe which contains 28 tablets. Within these 28 tablets, 24 of them had both 1 mg of norethindrone acetate and 20 mcg ethinyl estradiol.  The other 4 tablet contain 75 mg ferrous furamate. In addition, the US FDA has also recently approved  LO LOESTRIN FE of Warner Chilcott.  Similar to Loestrin Fe, Lo Loestrin Fe has 28 tablets.  Two of the tablets were 75 mg ferrous fumarate.  Two of the tablets contained 10 mcg ethinyl estradiol.  Twenty-four of the tablets contained 1 mg of norethindrone and 10 mcg of ethinyl estradiol.  Lo Loestrin Fe has the lowest concentration of ethinyl estradiol (or estrogen) per pill compared to other oral hormonal contraceptive in the market.  Although it has been approved, the company has not yet launched the product.  It anticipates the product will be launched in early 2011.

• Earlier this year, Warner Chilcott and Watson entered into agreements in regards to several products.
• In short, Watson is allowed to market generic products of Loestrin(R) 24 Fe on the "earlier of January 22, 2014" or when another generic version of Loestrin 24 Fe enters the US market.
• Watson is allowed to market generic products of Femcon(r) Fe (norethindrone, ethinyl estradiol tablet, chewable and ferrous fumarate) either on the earlier of 180 days after the generic product from Barr Lab (now Teva Pharma) enters the market or on January 1, 2013.
• For further information, please refer to company website. 

According to Watson, it licensed this newly approved product from a subsidiary of Waner Chilcott plc.  Watson plans to actively market the product in the second quarter of 2011.  The product will be marketed by Watson's Global Brands division.

So the difference between Watson's product and Loestrin 24 Fe is the amount of norethindrone and ethinyl estradiol.

• Norethindrone is a progesterone.
• Ethinyl estradiol is an estrogen.

Clinical Data

•  The drug was approved based on the phase III multicenter, open-label study that lasted 12 months to evaluate the safety and efficacy of the product to prevent pregnancy. 
• The study enrolled 1251 women between the age of 18 and 35.  
• The results showed that patients in the trial had the Pearl Index of 2.01.  This score indicated that patients in the treatment had a 2.01 pregnancies if used by 100 women for one year.  Pearl Index is commonly utilized in clinical trial to report the effectiveness of a particular birth control method.
• In addition, patients also reported shorter and predictable periods.   
• Most commonly seen adverse events were
• Nausea and vomiting: 8.8%
• Headaches/migraine: 7.5%
• Depression/mood complaints: 4.1%
• Dysmenorrhea: 3.9%
• Acne: 3.2%
• Anxiety symptoms: 2.4%
• Breast pain/tenderness: 2.4%
• Increased weight: 2.3%

 Thoughts of Mine

While I think it's interesting and probably fine to include Iron in birth control pill, I don't know how more beneficial it is compared to other birth control products.  I am interested in learning why companies put iron into the product but they don't seem to measure the iron concentration.  Are they trying to demonstrate patients taking this product will less likely experience iron deficiency?  If so, they need comparative data.  Until then, it might be just speculative in regard to the benefit of iron in the product.

The contraceptive market is just so lucrative.  The US contraceptive market makes over 4 billion a year.  This makes companies want to come in and take shares from other existing products.  I guess they might be running out of the possible combination of progesteorne and estradiol.  That's probably why we start to see folic acid and iron being added into birth control pills.  Theoretically, they have not no harm as of now.  However, the benefits over existing products have not been specifically measured as seen in this product.  So are they really any better than the existing products? 

Bottom line: I don't think the product will have much impact in the market.  It might be chewable but most people don't have problems swallowing pills (they are quite tiny).  Unless they do a comparative study or have a great marketing team to make others believe that most of women are iron deficient, their shares might be large.  Also, don't forget, it will also be competing with Warner Chilcott's products.

If you were to design a birth control pill, how would you want them to be?  

Sunesis has initiated the phase III study (VALOR) using its vosaroxin in combination with cytarabine in patients with first relapsed or refractory acute myeloid leukemia treatment of acute myeloid leukemia (AML)

Sunesis has initiated the phase III study (VALOR) using its vosaroxin in combination with cytarabine in patients with first relapsed or refractory acute myeloid leukemia  treatment of acute myeloid leukemia (AML).

This post includes:

• Information about vosaroxin
• Information about clinical trial design
• Information about agreement and patents
• Information about past clinical experiences

About vosaroxin

• vosaroxin is a quinolone derivative and is formerly known as voreloxin.  It inhibit topoisomerase II activity by intercalating with the host DNA.  This results in the DNA double-strand breakage and stops the DNA replication.   As a result, the cell cycle will be arrested and cells will go through apoptosis - or cell death.
• The USFDA has granted an orphan drug designation to voreloxin for the treatment of AML in December 2009.

Study design:

• It's a multinational, randomized, double-blind, placebo-controlled, pivotal trial.  The company expects to enroll 450 patients in various sites across the world: The US, Canada, Europe, Australia and New Zealand.  The trial is an adaptive design.  An Independent Data and Safety Monitoring Board (DSMB) will review a single interim analysis and decide whether a one-time sample size adjustment is needed to maintain adequate power to provide statistically significant and clinically meaningful survival outcomes.  If the decision is made that an adjustment was needed, an additional 225 additional evaluable patients would be required to maintain adequate power.  The interim analysis is expected to take place in the middle of 2012.
• Once enrolled, patients will be randomized into either the vosaroxin group or the placebo group at a one-to-one ratio.  
• On day one and day four of each cycle treatment, patient will receive either vosaroxin or placebo depending on her/his respective assignment.  In addition, all patients will receive cytarabine daily for 5 days in each treatment cycle.  
•  Patients will be treated either with 1 or 2 cycles.
• If patients have complete remission or complete remission with incomplete platelet recovery, patients will be eligible to enter the consolidation phase of the treatment.    Patients will receive one or two cycles of chemotherapy.  
• After that, patients will followed for survival analysis.
• Dose: 
• Vosaroxin is given as 10-minute infusion at 90 mg/ m2 on days 1 and 4
• cytarabine is given as 2-hour intravenous infusion at 1 g/ m2 on days 1 through 5
• The study primary endpoint: overall survival.
• The study secondary endpoint: Complete remission rate and safety and tolerability
• The study also has tertiary endpoints

Agreement and Patents:

• In 2003, Sunesis licensed worldwide development and commercialization rights to veroloxin from Dainippon Sumitomo Pharma Co. Ltd.
• Dainippon was entitled to receive up to 7.5 M from Sunesis once the company started phase III clinical testing, filing for a new drug application and receiving regulatory approval in the US, Europe and Japan for the treatment of cancer. Dainippon is also eligible to receive royalty payments from Sunesis based on total annual net sales of voreloxin.
• Dainippon is entitled to receive other milestone payments if voreloxin is approved for indications other than cancer.
• Currently, Sunesis does not have capabilities to manufacture commercial scale. It's currently employing third party manufacturers to provide voreloxin active pharmaceutical ingredient and the finished drug product incorporating the API (active pharmaceutical ingredient).
• The company has an exclusive license to 44 issued composition-of-matter patents covering voreloxin drug substances.
• The US composition-of-matter patent is to expire in October 2015.
• Most of foreign composition-of-matter patents are to expire in June 2015.

Clinical Trial Information

• Phase 1b/2 clinical trial was conducted in patients with relapsed/refractory AML to evaluate the use of voreloxin in combination with cytarabine showed that the preliminary median overall survival was 7.8 months.  
• Complete remission rate was 27% and complete remission without full platelet recovery was 2%
• The most common grade 3 or higher non-hematologic adverse events were infection-related toxicities.
• By day 30, all-cause mortality was 2%
• By day 60, all cause mortality was 8%
•  Sunesis has also conducted a phase 2 trial using voreloxin in previously untreated elderly AML patients.  REVEAL-1 trial.
• The study used 3 different dosing schedules: A, B and C
• Schedule A: voreloxin was given once a week for three weeks
• Schedule B: voreloxin was given once a week for two weeks
• Schedule C: voreloxin was given on days one and four at either 72 mg/m2 or 90 mg/m2
• Median survival showed
• Schedule A: 8.7 months
• Schedule B: 5.8 months
• Schedule C: 7.7 months (at 72 mg/m2)
• One year survival
• Schedule A: 38%
• Schedule C: 38%
• Response rate for patients in Schedule C: 38%
• By day 30, all cause mortality was 7% in schedule C
• By day 60, all cause mortality was 17% in schedule C
• The most common grade 3 or higher non-hematologic adverse events were upper gastrointestinal mucosal inflammation and infection.
• Sunesis has also conducted a phase II trial using voreloxin as a single agent in women who have platinum-resistant ovarian cancer.
•  Patients were divided into 3 cohorts:
• Cohort A: 48 mg/m2 given every 3 weeks
• Cohort B: 60 mg/m2 given every 4 weeks
• Cohort C: 75 mg/m2 given every 4 weeks
• Overall response rate was 11% for each cohort.
• Median progression free survival
• Cohort A: 82 days
• Cohort B: 85 days
• Cohort C: 109 days (preliminary)
• Overall progression free survival was significantly higher in Cohort B and C patients than Cohort A patients.
• Most common grade 3 or higher adverse events (> 10% patients experienced) were neutropenia, febrile neutropenia and anemia.

Chelsea to accelerate the NDA submission of Northera

Chelsea Therapeutics is to file for the US marketing approval of Northera for the treatment of symptomatic Neurogenic Orthostatic Hypotension in the second of 2011.

About Northera

• Northera is the proposed brand name of droxidopa, a synthetic catecholamine that can be converted into norepinephrine via decarboxylation.  Norepinephrine is an important neurotransmitter and hormone in the body. It works to vasoconstrict the blood vessels in order to increase the blood pressure in the body.  Norepinephrine is often released during the stress situation in order to mobilize resources in the body.  In situation such as fight or flight response is necessary, the concentration of norepinephrine increases.  This is also in association with the stimulation of the sympathetic nervouse system. 

• It's being formulated as the controlled release formulation.

• When I first heard about the generic name of this drug, droxidopa, the first thing came to my mind is that it has something to do with Dementia or Alzheimer's disease because of the familiar names levodopa and carbidopa. When I read and realize it is used in symptomatic Neurogenic Orthostatic Hypotension, I am a bit shocked but then this medication if approved is indicated as followed:  NOH associated with Parkinson's disease, multiple system atrophy and pure autonomic failure. 

• Northera has been given Orphan Drug Status Designation and had Fast Track Designation by the FDA.  

Marketing and Regulation

• Droxidopa has been marketed in Japan by Dainippon Sumitomo Pharma since 1989 for the treatment of frozen gait or dizziness associated with Parkinson's disease.  In addition, it is also approved in treatment for the treatment of orthostatic hypotension, syncope or dizziness associated with Shy-Drager syndrome and Familial Amyloidotic Polyneuropathy.  In 2000, additional indications have been added in Japan for its use in the treatment of vertigo, dizziness and weakness associated with orthostatic hypotension in hemodialysis patients.
• In May 2006, Chelsea and Dainippon entered into an agreement to obtain a worldwide, exclusive, sub-licensable license and rights to certain intellectual property and proprietary information in regard to droxidopa.  Chelsea has paid Dainippon $100,000 upfront and issued 63,131 shares (note to myself: if ever involved in these deals I will try to make these shares even number!) of its common stocks at the price of appxoximately 4.35 per share.  In 2008, as Chelsea achieved a new milestone in the development of droxipoda (dosing patient in the phase III trial), it has paid Dainippon a total of $500,000.  Dainippon is entitled to receive royalty payments as well as milestone payments based on the signed contract.  According to the company annual report, Dainippon is entitled to receive up to another 3.25 M as of December 31, 2009. 

Currently, treatments for NOH are limited.   Some of the approaches are listed as below: (based on an article written by Roy Freeman, M.B, Ch.B. published in the New England Journal of Medicine called Neurogenic Orthostatic Hypotension on Feb 7, 2008)

• Non-pharmacological interventions: (not a complete list)
•  increase fluid and salt intake: 10 mg sodium a day and 2.0 to 2.5 L of liquid intakes are recommended.
• drink water rapidly: rapid ingestion of 0.5L of water can raise blood pressure within 5-15 minutes
• wear custom-fitted elastic stockings and abdominal binder
• Raise the head of the bed by 10-20 degrees
• perform isotonic exercise
• and others: please refer to the article for more information

• Pharmacological interventions:
•  volume-expanding agent: 9-alpha-fluorohydrocortisone
• midodrine: a diect alpha-1 adrenoreceptor agonist => increase peripheral vasoconstriction
• pseudoephedrine
• ephedrine
• desmopressine acetate
• Erythropoietin: increase red blood cell concentrations
• pyridostigmine: acetylcholineesterase inhibitor to decrease the destruction of important neurotransmitters

Clinical trials

• The company has completed the two phase III trials called Study 301 and Study 302.  The pre-NDA meeting with the FDA has been completed and the FDA only requires safety data from a QTc study as well as a post-marketing study to evaluate the use of Northera in patients with renal dysfunction.
•  Study 301: the phase III trial evaluating the safety and efficacy of Northera against placebo in patients suffering from primary autonomic failure.  The study enrolled over 160 patients.
• Study design
• Initially, patients entered an open-label dose titration period for 7 days.  During this phase, patients were treated with Northera for up to 600 mg three times a day.  In addition, patients needed to demonstrate both a blood pressure and symptomatic improvement before entering the blinded study.  If any of the above conditions was not satisfied, patients were not eligible to enter the blinded study.
• Patient then were randomized into either the placebo group or the Northera treatment group for 7 days.  Patients would either receive placebo or Northera depending on their designated treatment group.  The composite orthostatis hypotension questionaire was used to measure changes in symptomatic benefit was used at the end of the blinded period.
•  The study primary endpoint:  improvement in symptoms associated with neurogenic hypotension.  The endpoint is measured using the orthostatic hypotension questionarie.
• The preliminary result showed that a "clinically meaningful and statistically significant improvement in symptoms associated with neurogenic orthostatic hypotension was observed in the Northera group when compared to the placebo group (p=0.003)
• Of the most common adverse events, headache was most frequently observed in the Northera group with the rate of 7.4%.
• Study 302: It's a pivotal Proof of Efficacy - Withdrawal Design.  An extension study which included long-term efficacy assessment after 3 months of study 302 currently ongoing.
• Study Design:  It's a randomized, placebo-controlled trial to study the safety and efficacy of droxidopa against placebo in patients who have primary autonomic failure, dopamine beta hydroxylase deficiency or non-diabetic neuropathy and symptomatic NOH.  
• Initially, all patients were entered into the dose-titrating period during which all patients received droxidopa. Patients who demonstrated symptomatic benefit AND improvement in blood pressure were allowed to be in the open-label portion of the study.  After this, patients were randomized into either a placebo group or a droxipoda group in a one to one ratio for 14 days.
• The Study Primary Endpoint:  change in the mean score of item 1 (dizziness and light-headedness in the Orthostatic Hypotension Symptom Assessment 14 days following randomization to continued therapy with droxidopa or placebo.  
• The results showed that at the end of the 14-day period, the use of droxipoda did not significantly improve dizziness or light-headedness (Item 1 in the Orthostatic Hypotension Symptom Assessment).  So basically, it did not meet the primary end point.

Note from me: It's interesting that even though one of the phase III trials did not meet its primary endpoint, Chelsea after meeting with the FDA has decided to accelerate the NDA process.  Given that the 301 study measured probably better efficacy endpoint (the composite score) rather than just one item in the OHSA, it probably has more significant impact than the 302 study.  Its long term safety profile has been demonstrated in Japan with no significant adverse events.  Given the limited treatment option, I expect this drug will probably get a nod from the FDA next year after the company submits its NDA.

The USFDA declines to approve AstraZeneca's Brilinta for the treatment of Acute Coronary Syndromes

The USFDA issued a complete response letter to AstraZeneca indicating that it could not approve Brilinta, the proposed brand name of ticagrelor tablet, for the treatment of Acute Coronary Syndromes.

Early in the month, the European Commmission has granted AstraZeneca to market Brilique (the proposed brand name of ticagrelor tablet in Europe) for the treatment of Acute Coronary Syndromes (ACS). With this approval, AstraZeneca is now able to market Brilique in 27 countries that belong to the European Union. AstraZeneca plans to initiate the launch of Brilique in 2011.

AstraZeneca has completed the phase III trial comparing the use of ticagrelor against clopidogrel in conjunction with aspirin to see which one is better at reducing deaths from vascular causes, future, heart attacks and/or strokes in patients with ACS (the trial ID: NCT00391872).

The complete title of the trial is called: A randomized, double-blind, parallel group, phase III, efficacy and safety study of AZD6140 (ticagrelor) compared with clopidogrel for prevention of vascular events in patients with Non-ST or ST elevation acute coronary syndromes (ACS). The short name for this study is PLATO – A study of PLATelet inhibition and Patient Outcomes.

The primary outcome of the study is to compare AZD6140 to clopidogrel in non-ST or ST elevation ACS in the reduction in relative risk of vascular death, non-fatal myocardial infarction, or nonftal stroke.

The study was initiated in October 2006 and completed in March 2009. The study enrolled over 18,000 patients. Patients were randomized into either a ticagrelor and placebo group or a clopidogrel and placebo group at a 1 to 1 ratio. The loading dose of clopidogrel was 300 mg. The loading dose of ticagrelor was 180 mg.

In the ticagrelor group, after the loading dose, patient was instructed to take ticagrelor 90 mg twice a day for 6 to 12 months.

In the clopidogrel group, after the loading dose, patient was instructed to take clopidogrel 75 mg once a day for 6 to 12 months.

Patients in both groups also took aspirin in conjunction with their antiplatelet therapies.

The study results were published in the New England Journal of Medicine on September 10, 2009.  They showed that

•  A significantly lower of composite death (caused by vascular causes, myocardial infarction or stroke) was observed in the ticagrelor group when compared to the clopidogrel group (9.8% vs 11.7%, HR: 0.84; 95%CI: 0.77 to 0.92, p< 0.001).
• A significantly higher rate of major bleeding not related to coronary-artery bypass grafting was observed in the ticagrelor group when compared to the clopidogrel group (4.5% vs 3.8%, P=0.03).  More incidence of fatal intracranial bleeding was observed in the ticagrelor group.

Many subgroup analyses have been conducted.  The followings are just a few recently posted.

The result showed that patients whose doctors planned to perform invasive strategy (about 13,408 patients out of 18,624 enrolled patients) in the ticagrelor group experienced significantly less cardiovascular death, myocardial infarction or stroke when compared to patients in the clopidogrel group (9.0% vs 10.7%, hazard ratio 0.84, 95% CI 0.75 – 0.94 : for those interested in statistics)

• The rates of total major bleeding were not significantly different between the two groups (11.6% vs 11.5%, p = 0.8803).

• The rates of severe bleeding were not significantly different between the two groups (3.2% vs 2.9%, p= 0.3785)

In a subgroup analysis in patients who has renal dysfunction, samples of 15,202 patients were analyzed. Renal dysfunction was defined as having creatinine clearance less than 60 ml/min. The results showed that

• Patients with chronic kidney diseases experienced a more significant reduction in ischemic endpoints in ticagrelor group than patients in the clopidogrel group.
• Patients with chronic kidney diseases also experienced a significantly lower mortality in ticagrelor group than in patients in the clopidogrel group (10.05% vs 14.%, HR: 0.72, 95% CI: 0.58 to 0.89)

About ticagrelor

• Ticagrelor is a direct-acting P2Y12 receptor antagonist.  It reversibly binds to ADP receptor and antagonizes it. (It's the first in its class)
• Clopidogrel is an antiplatelet agent.  Unlike ticagrelor, clopidogrel irreversibly bind to the ADP receptors on the platelet surface.  
• The effect of antagonizing the ADP receptor (the P2Y12 component of the receptor)
• This leads to the prevention of activationg the GPIIb/IIIa receptor complex.  Hence, reduction of platelet aggregation is observed.

Top Drug Pronunciation is now on Youtube

Hello there...

It's been awhile since I posted anything related to the top 200 drug pronunciation.  The change has come! 

With the introduction of the youtube channel a few months ago, I've decided to use it as a learning tool as well. 

Each video will be dedicated to one drug.  There, you will be able to learn about the generic name/brand/therapeutic classification/indication (general).

So head over there to learn some drug!

The first one: abacavir/lamivudine - Epzicom!



Best,

Pharmapodia