BioCryst released results of its phase III data for peramivir and proposed changes in the other phase III trial

BioCryst Pharmaceuticals released the result of its phase III study using peramivir in the treatment patients hospitalized with influenza.
About the study:

• A phase III safety and virology study (named 303) was an open-label, randomized trial that evaluated the safety and tolerability of peramivir given intravenously as once-a-day infusion of 600 mg or a twice-a-day infusion of 300 mg.
• Patient population: adult and adolescent patients who were hospitalized with confirmed or suspected influenza infection.
• Treatment duration: 5 to 10 days
• Number of patients enrolled: 234
• Patients Age: 14 to 92
• % of patients having illness more than 48 hours: 85%
• The number patients who were administered with peramivir: 230.  Of these 230 patients, 170 were previously treated with oseltamivir.
• Primary endpoint: change in the influenza virus titer in nasopharyngeal samples measured by Log10TCID50 – log10 tissue culture infective dose50

Results in short:

• This is interesting: so according to the press release only 44 patients had a positive baseline culture.  So the actual number of patients that the result will be based on is 44.  Of the 44 patients, 20 patients were randomized into the 300 mg twice daily group and 24 patients were randomized into the 600 mg once a day group.  The result showed that
• Twice a day group: there is a 1.66 reduction in log10 TCID50 viral titer (95% CI -2.32, -0.61)
• Daily group: there is a 1.47 reduction in log10 TCID50 viral titer (95% CI -1.89, -0.75)
• Other results reported when the company combined results from the patients who had positive viral titer in nasopharyngeal cultures and patients who had influenza confirmed by other methods (RT-PCR, viral culture, or serology):

• Median time to resolution of fever: 25.3 hrs
• Time to clinical resolution: 92 hours (about 4 days)
• Time to alleviation of symptoms: 145 hours (about 5-6 days)
• Time to resumption of usual activities: 26.8 days

What can we say about this result? Although it demonstrates statistically significant in the reduction of viral titer in nasopharyngeal samples, I am unsure about the clinical significance in this case.  The data did not indicate as whether this medication is better than currently available therapies.  Stating number doesn’t usually mean a lot unless there is something to compare to.  It’s clear that a reduction in virus titer in the nasopharyngeal has been observed.  However, of all the 230 patients who were administered with peramivir, only 44 patients who were positive for virus in the nasopharyngeal samples.  This is less than 25% of the enrolled patients.  This might justify why the company wants to increase the number of patients being evaluated in the next phase III trial.

Further development

• In addition to releasing the results, the company has submitted a proposal to the US Department of Health & Human Services (HHS) to revise its other phase III protocol (named 301).  The followings are in the proposal:
• Focus of primary efficacy analysis will be on the subset of patients who are not treated with neuraminidase inhibitors
• Increase the total number of enrolled patients and increase total number of clinical trial sites
• Increase geographic regions
• Extend enrollment timeline to beyond the end of 2011

About peramivir:

• Peramivir, discovered by BioCryst, is a neuraminidase inhibitor.  
• It was launched in Japan as RAPIACTA in January 2010 by Shionogi & co. LTD.  
• In August 2010, Korea Food and Drug Administration has given Green Cross marketing and manufacturing authorization for IV peramivir to treat patients who are infected with influenza A and B viruses, including H1N1 and avian influenza.

Collaboration

• BioCryst and Shionogi signed an exclusive license agreement in March 2007.  Under the agreement, Shionogi has exclusive rights to develop and commercialize peramivir in Japan for the treatment of seasonal and potential life-threatening human influenza.
• BioCryst and Green Cross signed an agreement in June 2006 under which Green Cross is responsible for conducting clinical trials in South Korea and BioCryst is entitled to use these data for its clinical studies program.
• Based on the gathered information, BioCryst has exclusive rights to develop and commercialize peramivir worldwide except Japan, Taiwan and south Korea.

The FDA limits the amount of acetaminophen in prescription combination products

The FDA limits the amount of acetaminophen in prescription combination products to a maximum of 325 milligrams (mg) in each tablet or capsule or other dosage unit.  In addition, products containing acetaminophen and other active ingredients will now carry a boxed warning indicating the following

•  Potential severe livery injury

Acetaminophen or APAP containing products that are available by prescription will also carry a warning for potential allergic reactions such as swelling of the face, mouth, and throat, difficulty breathing, itching or rash.

The FDA plans to complete the dose reduction in combination products in three years in order to eliminate the shortage of the medications upon the news release.  

Remember: this new safety measure is only applicable to acetaminophen combination products that are only available through prescription and not over the counter products.  Although acetaminophen-containing-OTC products are not affected by this new measure, the FDA indicates that it’s currently working to reduce the risk of acetaminophen related liver injury from OTC products.

About acetaminophen:

• Acetaminophen is an analgesic.  The exact mechanism or how this drug works is currently unknown.  However, it’s speculated that it has to do with the reduction in the amount of prostaglandins. 
• Acetaminophen can work to relieve pain and reduce fever 
• Although it’s mostly available in tablet/capsule/solution, a new IV formulation has been approved and is now available in the US.  The brand name for the IV formulation is Ofirmev which is marketed by Cadence Pharmaceuticals. 
• When used inappropriately, acetaminophen can cause liver injury.  Hence a boxed warning has been added to the over-the-counter product.  Now, the boxed warning will be added to the combination products that are available via prescription.

·         Considerations when taking products containing acetaminophen

o   Avoid alcohol when taking this medication because it can increase the risk of liver injury

o   Do not take more than the recommended amount. 

§  For normal adult patient: do not take over 4 g. 

§  For patient with liver injury: do not take more than 2 g of acetaminophen.  Need to consult with physicians before taking acetaminophen.

o   Do not take more than one product containing acetaminophen because it can lead to overdose.  Always tell your pharmacists or physicians which medications you are taking in order to avoid acetaminophen overdose

o   If an adult patient is currently taking acetaminophen over-the-counter to treat pain or fever but neither one subsides within 10 or 3 days respectively, patient needs to contact physician.

GlaxoSmithKline and ChemoCentryx initiate phase III trial of GSK786 in patients with Crohn's disease

Treatment for the first patient with Crohn's disease in the phase III trial using GSK786 has been initiated.  The phase III trial is a randomized, double-blind, placebo-controlled trial that is designed to compare the safety and efficacy of GSK786 to placebo in the treatment of Crohn's disease. 

About the study:

• The study plans to enroll approximately 600 patients
• Dose of GSK786 that will be given to patient is 500 mg once a day or twice a day
• Patient population: moderately-to-severely active Crohn's disease.
• Primary endpoint: proportion of subjects achieving a treatment-induced clinical response using the Crohn's Disease Activity Index (CDAI)
• Secondary endpoint: Proportion of subjects achieving clinical remission

 About GSK786

• GSK786 is formerly known as Traficet-EN(TM)
• It is an orally available CCR9 antagonist.  It works to block the action of ligand (T-cell) responsible to activate the CCR9 receptor which plays an important role in the uncontrolled inflammation that is thought to occur in Crohn's disease.  As a result, it will help reduce the inflammation while does not depress the immune system by depleting T-cells.

Agreement:

• It was originally developed by ChemoCentryx which had completed a multinational phase II study called PROTECT-1 (Prospective Randomized Oral Therapy Evaluation in Crohn's disease Trial).  The result showed that GSK786 (or formerly known as CCX282-B) showed significant clinical efficacy in the reduction of disease severity during the induction phase.  It was also shown to be clinically efficacious in maintaining the remission in the studied patients (moderate-to-severe Crohn's disease).
• On January 11, 2010, GSK has announced that it is to obtain exclusive license to further develop and commercialize Traficet-EN worldwide.  Based on the original agreement, ChemoCentryx is entitled to receive $35 Million and may also be eligible for future milestone payments.
• On August 24, 2006, GSK and ChemoCentryx entered a worldwide multi-target strategic alliance to discover, develop and market "novel medicines targeting four chemokine and chemoattractant receptors for the treatment of a variety of inflammatory disorders".   Under the alliance, GSK will have access to selected compounds.  The alliance is formed through GSK's Center of Excellence for External Drug Discovery (CEEDD).  Once signed, an upfront payment of 63.5 M was made to ChemoCentryx.  This came in form of cash and equity investment (Series D financing).  Based on the agreement, ChemoCentryx is entitled to receive up to $1.5 billion in milestone payments if all six production options are successfully developed and commercialized.  In addition, if ChemoCentryx is to offer initial public offering, GSK will be required to invest in its common stock. 
• Under the terms of agreement, the discovery and development of small molecule drug candidates will be solely ChemoCentryx's responsibilities.  Once the molecules go through clinical proof of concept, GSK will then have exclusive options to license each product for further development and commercialization.  In the case of Traficet-EN, GSK has exercised its option.  In regard to Traficet-EN, ChemoCentryx has option to co-develop and to co-promote Traficet-EN in Irritable Bowel Disease to certain specialists in the US.

Watson got FDA Approval for Generic Version of Fentora

As reported in the January drug approval, the generic version of Cephalon's Fentora tablets has been approved.  Fentora is the brand name for fentanyl buccal tablet.  It is indicated to be used in adult cancer patients (18 years and older) who use opioid medicines for pain regularly and around the clock for constant cancer pain.

Watson's generic version of Fentora is available in 0.1, 0.2, 0.4, 0.6 and 0.8 mg buccal tablets.  Because this is the first generation application approved by the FDA for the generic version of Fentora, it may be entitled to have a 180-day period of market exclusivity.  This market exclusivity will only be made available if another ANDA was approved prior to 180 days after Watson's products are launched or the expiration of listed Orange Book patents comes to term.

Cephalon has filed a patent infringement lawsuit against Watson.  The lawsuit is currently pending in the US District Court for the District of Delaware.  Watson is currently waiting for the decision before launching the product.

About Fentora: taken from packet insert

Fentora is the brand name for fentanyl.  Fentanyl is an opioid that is classified as Schedule II drug.  It's available in 0.1, 0.2, 0.3, 0.4, 0.6 and 0.8 mg buccal tablets.

Contraindications:

• It is contraindicated in opioid non-tolerant patients.
• It is contraindicated in the management of acute or postoperative pain including headache/migraine
• It is contraindicated in patients who have known intolerance or hypersensitivity to any of its components or fentanyl
• For further details and information, please refer to the packet insert.

Boxed Warnings

• Deaths have been reported in patients using Fentora.  Deaths were due to improper patient selection or improper dosing.
• Fatal overdose can occur when patients or physicians substitute Fentora for other fentanyl products.
• do no substitute Fentora with any other fentanyl products.  Please consult initial dosing recommendation table in the packet insert for further details.  Death can occur if substitution was made without proper management.
• Due to its nature, fentanyl can be abused just as other schedule II opiod substances: morphine, oxycodone, hydromorphone, oxymorphone, and methadone.
• Keep all medications out of reach of children.

Manufacture

• According to the packet insert, it's currently being manufactured by Cephalone
• Fentora is currently the registered trademark of Cima Labs which is a subsidiary of Cephalon Inc.

January Drug Approval has been updated!

The New Year starts off with only a few drugs.  Maybe due to inclement weather in the East Coast, things might not have moved so fast. 

Here is the updated January list!

Older list can be accessed here!

Enjoy and stay safe!

Pharmapodia

December Drug Approval has been updated!

The FDA must have been pretty busy the last few days of the year.  I have just checked and a lot more products were added toward the end.

The December list has been updated and the Jan of 2012 is on the way!

Happy Reading! I definitely learn a lot of this process :)

Pharmapodia

The FDA has granted XL-184 of Exelixis an orphan drug designation

The FDA has granted XL184 of Exelixis an orphan drug designation for the treatment of follicular, medullary and anaplastic thyroid carcinoma, and metastatic or locally advanced papillary thyroid cancer.

XL184 also has been assigned a generic name: cabozantinib.

About XL 184 or cabozatinib

•  Cabozatinib is a MET and VEGFR2 inhibitor.  It works to inhibit tumor growth, metastasis and angiogenesis.
• MET receptor is a tyrosine kinase receptor.  It has been shown to be overexpressed in a number of cancer.  It has been shown that when this receptor is activated, it can cause change in mitosis, cellular morphology, and motogenic.  Its ligand is hepatocyte growth factor/scatter factor. Normally, this ligand-signaling complex is needed during embryonic development.
• VEGFR2 is also a tyrosine kinase receptor.  Upon activated by the vascular endothelial growth factor, it will stimulate the formation of endothelial cells.

Current Developments:

• It is currently in the phase 3 trial that assesses its safety and efficacy in patients with medullary thyroid cancer.  The company plans to release the top-line results in the first half of 2011.  It expects to file a new drug application (NDA) in the second half of 2011.
• It's being evaluated in patients with solid tumors including metastatic castration-resistant prostate cancer, ovarian cancer, melanoma, breast cancer, non-small cell lung cancer and hepatocellular cancer in phase II trial.
•  A phase II trial in patients with recurrent glioblastoma is ongoing
• Its use with or without erlotinib in patients with non-small cell lung cancer is currently being studied in the phase 1b/2 trial
• A phase I trial evaluates its use in combination with temozolomide and radiation therapy as initial treatment in patient with glioblastoma is currently ongoing
• A phase I trial in patients with renal cell carcinoma and differentiated thyroid cancer is ongoing.

Abstral of ProStrakan was approved for use in the US

It's been a wonderful break for me.  Vacation is now over and I'm back in full force.  Start off the year with a new drug approval!

The FDA has approved a new opioid analgesic called Abstral to manage pain in cancer patient.  Abstral is marketed by ProStrakan Inc (note: The FDA website listed the wrong company.  It's ProStrakan not Prostraken).  The full indication is listed as "It can be used for the management of breakthrough pain in cancer patients who are 18 years of age and older who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain."

About Abstral:

Abstral is the brand name for fentanyl and it is available as transmucosal tablets.  The medication is formulated to release fentanyl immediately when applied on the surface surfaces of the mouth, the nasal passages or the throat. 

• Fentanyl is a pure opioid agonist.  Other opiod agonists are morphine, oxycodone, hydromorphone, codeine and hydrocodone,

Launch and Commercialization:

• ProStrakan plans to launch this product in the first quarter 2011.  This will mark this as the second cancer product that is launched by ProStrakan in the US.
• 
  
• Abstral is currently available in Europe in the following countries:  UK, Germany, France, Spain, Italy and Sweden.  In its first year, Abstral has reached a 17 M pound sale mark in the UK, Germany, France and Spain.
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• It's manufactured by Recipharm Stockholm AB

Prescribing Information:

• In order to minimize the risk of misuse, abuse, addiction and overdose, restriction has been put on Abstral.  Its availability is limited through a Risk Evaluation and Mitigation Strategy program. This makes it the first product to be approved in the US that belongs to the FDA mandated class-wide risk Evaluation and Mitigation Strategy (REMS) for transmucosal immediate release fentanyl products.
• 
  
• Under the REMS program, pharmacies, distributors and health care professionals who prescribe this medication to outpatients need to enroll in the program in order to prescribe, dispense and distribute this product.  Components of the REMS document include: the Patient-Prescriber Agreement and the enrollment form.
•  
• It should not be taken with alcohol without doctor approval.  It should not be taken with grapefruit juice due to increase in side effects.

Pregnancy and Breast Feeding:

• It should not be used in pregnancy unless specified by doctor.
• When taken, Fentanyl will be present in breast milk and it could cause extreme drowsiness and shallow breathing in breastfed child.  Use of Fentanyl during breast-feeding is not recommended.  However, patients need to consult physicians before making decisions.

How to take this medication: (based on the UK prescribing information Leaflet)

• It should be taken by placing the tablet under the tongue where it will dissolve rapidly and hence increase absorption.  
• Do not suck, chew or swallow the tablet
• Only remove the tablet when you are ready to use the medication. To remove the tablet, please follow the instruction by no trying to push it out through the foil top as with normal tablet.  Instead, patient should peel back the tab of the foil top of one blister and gently remove the tablet.
• Avoid drinking or eating until the tablet has completely dissolved under your tongue
• Don't stop taking medication without telling your doctor

In case of overdose

• Call your physician, pharmacist, local hospital immediately
• Remove the remaining tablet in the mouth
• Talk to someone while waiting for help to come.
• Observe the following symptoms because they are signs of overdose: extreme drowsiness, slow and shallow breathing

Adverse Reactions:

• Very Common Side effects (occur in more than 1 patient in 10)
• Nausea, Drowsiness, dizziness and Headache.
• Common Side Effects (occur in 1 to 10 patients in 100)
• vomiting, diarrhea, constipation,  stomach ache and many others.
• Serious Adverse Events: Deaths when the drugs are used improperly due to patient selection or dosing

Storage

• Do not store at temperature above 25oC
• Store medication in original blister
• Protect the medication from moisture
• Should take the medication to pharmacy for disposal

Enrollment of the phase 1/2 trial using ISV-303 in patients going through ocular surgery has been completed

InSite Vision announced that it has completed patient enrollment for the phase ½ study using ISV-303 to reduce pain and inflammation associated with ocular surgery.

About the study:

The phase ½ trial started patient enrollment in August. About 160 eligible patients undergoing cataract surgery were enrolled into the study. The study aims to evaluate the safety and efficacy of ISV-303 administered once a day or twice a day.

The study had 4 arms that patients were randomized into: ISV-303, commercial bromfenac once a day, commercial bromfenac twice a day and vehicle (DuraSite).

The company plans to release top-line results in the first half of 2011.

About ISV-303:

ISV-303 combines a low dose of bromfenac with InSite Vision's prioprietary DuraSite(R) technology. This allows the drug to stay longer on the eye surface to improve penetration. Bromfenac is a non-steroidal anti-inflammatory.

Bromfenac is currently marketed under two brand names Bromday and Xibrom by ISTA Pharmaceuticals.

DuraSite is a bioadhesive polymer core technology. It was developed by InSite Vision and it is used to increase drug retention on the surface of the eye. This can potentially lead to a decrease in drug administration frequency.

Future plan:

InSite Vision plans to initiate the phase III trial using the results from this phase ½ trial.