Cell Therapeutics appealed FDA's deicision on its New Drug Application for pixantrone.

Cell Therapeutics formally appealed FDA's decision in regard to its New Drug Application for Pixantrone. The FDA is expected to reveal its decision in the first quarter of 2011.

On April 2010, Cell Therapeutics received a complete response letter from the FDA stating that the FDA could not approve pixatrone dimaleate (which would have been mareted as Pixuvri) for the treatment of relapsed or refractory aggressive non-Hodgkin's Lymphoma (NHL).  The agency requires additional clinical trial to be conducted because efficacy has not been demonstrated in the submitted trials.  However, due to limited therapeutic options, the FDA has allowed Cell Therapeutics make the drug available to selected patients while the company plans to conduct further trials to fulfill the FDA's requirement. 

• Since April, the company has met the FDA and filed for Special Protocol Assessment (SPA) for pixantrone for the treatment of relapsed or refractory aggressive B-cell Non-Hodgkin's Lymphoma in August 2010. The second registrational trial is called PIX306.
• In June 2010, the company announced the results from its phase III pivotal trial PIX301 using pixantrone dimaleate for the treatment of relapsed or refractory, aggressive non-Hodgkin's lymphoma.  The results showed pixantrone was able to increase patients' progression-free survival by 2 months.  However, patients' overall survival was not significantly different between the use of pixantrone and its comparators.  This can be thought of as pixantrone was not able to extend patients' overall survive more than current therapies.
• From the trial: common sides effects (>10% and grade 3/4): neutropenia and leukopenia.  The number of patients experienced grade 3 or greater cardiac events were 5 in the pixantrone group, 4 more than the comparator arm.

Meanwhile, it is a different story on a different shore.  After receiving positive opinions from the European Regulatory Authorities and European Pediatric Committee, Cell Therapeutics submitted the Expanded Pediatric Investigation Plan in the EU.  In November 2010, Cell Therapeutics finally submitted European Marketing Authorization Application for Pixuvri.  The European Medicines Agency has validated the application and the review process has begun.  If approved, Pixuvri will be marketable in the European Member States.  In addition, the company plans to to submit a marketing application in other selected European countries starting with Switzerland.

So what is Pixantrone?

•  Pixantrone is an aza-anthracenedione whose structure is similar to anthracycline like doxorubicin.  Anthracyclines are topoisomerase II inhibitors which work to cause double-stranded DNA breakage and lead to cell death. Even though the two share similarities, pixantrone forms stable DNA adducts after alkylating with the FDAs.  It targets the CpG rich, hyper-methylated sites.   Anthracyclines have been known to cause cardiac toxicity.  Pixantrone is also suspected to cause the same adverse event even though pixantrone has been designed to prevent the binding of the drug and iron in addition to prevent the prepetuation of superoxide production.  Hence, patients need to be monitored for cardiac toxicity besides other common ones until further trial has been completed and assessed.
• Since May 2009, pixantrone has been available in Europe as an investigational drug on a named-patient basis.

Merck Acquired SmartCells (and a small note on Diabetes)

Seriously since the beginning of this week, how many acquisitions have been reported?  Shopping spree I guess.

On December 2, 2010, Merck and SmartCells Inc have entered into a definitive agreement under which Merck will acquire all SmartCells' outstanding stock.  Merck will make upfront cash payment to SmartCells shareholders who are entitled to receive clinical development and regulatory milestones for potential products related in the transaction that could be worth up to $500 M.

 What does Smartcells do?

• SmartCells develops a technology which it calls SmartInsulin.  It was originally developed from MIT.  SmartCells has exclusive license to the technology.
• SmartInsulin is a layered, biocompatible and biodegradable polymertherapeutic that can be attached to a glucose-binding molecule.  In the case of diabetes, when the body glucose concentration reaches a certain level, insulin from SmartInsulin will be released.  As insulin is released into the blood stream, it will interact with the receptors on the cells in order to lower the blood glucose concentration.
• SmartInsulin technology can be applied in other therapeutic areas such as endocrine disorders, oncology or cardiology.

Note about Diabetes:
Obesity and diabetes are current and future healthcare problems.  According to the CDC, approximately 2 million people in the US had diabetes in 1958.  Half a century later (2007), almost 23.6 million people in the US had diabetes.  This constituted about 7.8% of the US population.  However, this rate will continue to climb.

Diabetes come with different flavors of complications

• Heart Disease and Stroke:  Diabetes patient has 2 to 4 times increase risk of stroke
• High Blood Pressure:  The Joint National Committee (JNC7) recommended a lower blood pressure requirement for patients with diabetes.  Majority of diabetes patients have high blood pressure (75%).  This definitely is higher than national average. (I can't imagine 75% of the US population have high blood pressure.  The ER visits might increase significantly especially with leaked news coming out everyday!)
• Blindness:  One complication that could directly patient's quality of life. Of all the things that one can lose, eyesight can be the hardest thing to part.  Due to its ability to damage nerve, about 12,000 to 24,000 new cases of blindness attributed to diabetic neuropathy are diagnosed each year.
• Kidney Disease:  The leading cause of kidney failure is diabetes. Without a proper kidney, one cannot eliminate certain toxin in the body.  The body chemical composition will be disturbed and other complications can incur.
• Nervous system:  nerve damage is common in patients with diabetes.
• Amputations:  
• Dental Disease
• Complications of Pregnancy
• and the list goes on...

Efforts have been made to control obesity epidemic.  However, little progress has been observed.  As a result, pharmaceutical companies continue to come up with different medicines and ways to treat this chronic condition.

Diets play important roles in both obesity and diabetes.  Healthy diets have been encouraged.  However, I think it's easier said than done.  Fast food and package food are so convenient that unless cooking is your joy, the attractiveness of quick and easy meals is overwhelming.  So until then, I hope you can pack some good and nutritious snacks in your purses, backpack, or bag.  I don't know how many times the temptation to buy a chip bag at the airport or the convenient store is so overwhelming that without a small apple I would have swallowed a whole bag of potato chip in a blink.  So help yourself and help the next generation, bring an apple/orange/or anything that you love and don't mind eating/peeling/washing.  It will make you feel better.

Baxter and Takeda entered a Development, License and Technology Transfer Agreement of Vero cell-technology in Japan

• Baxter and Takeda have completed a Development, License and Technology Transfer Agreement.  Under the agreement, Takeda will have exclusive license to Baxter’s proprietary Vero cell-based influenza vaccine technology in Japan.  They will jointly pursue the development of an H5N1 influenza vaccine in Japan.  In addition, Baxter will help Takeda securing government funding for the construction of manufacturing facilities of Vero cell-based influenza in Japan.  According to the term of the agreement, Takeda expects to be able to manufacture the H5N1 influenza vaccine at full-scale by the end of Takeda’s 2013 fiscal year which will end on March 31, 2014.
• In conjunction to an upfront cash payment to Baxter, Baxter is entitled to receive the following payments from: development cost reimbursement, achievement of certain milestones (regulatory and commercial), technology transfer, as well as royalties on sale the vaccine in Japan.  Financial terms have not been disclosed.
• So what is Vero cell?
•  Vero cell was derived from a kidney of a normal adult African Green monkey by y. Yasumura and Y. Kawakita at the Chiba University in Japan in 1962.  In 1964, Dr. B. Simizu brought the cell line passage level 93 (meaning the 93th generation of the cell line) to the Laboratory of Tropical Virology, NIAID, NIH.  Without getting into further complicated information, ever since it was developed and manufactured, Vero cells have been used worldwide to produce human vaccine e.g. polio and rabies.  Vero cell line is a continuous cell line (meaning it can grow continuously in culture).  Being an aneuploid cell, its ability to adapt for growth in bioreactors is higher than diploid cells.  In addition, it is also able to provide consistently high viral yields. In immunosuppressed rodent models, Vero cell line does not cause tumor formation.
• Vero cell technology:
• Baxter has developed technology that incorporates Vero cell which has been described above into the production of both seasonal and pandemic influenza vaccines.  According to Baxter’s claim, its technology is a “highly standardized, close production process” and “has high purity in the absence of antibiotics”.

Update from GSK: Avodart and ezogabine

A bad day for GSK?

• The FDA advisory committee declined to recommend GSK's Avodart or dutasteride for the use in reducing the risk of prostate cancer in men who are at risk of having the disease.  
• Dutasteride is a 5-alpha reductase inhibitor.  Five-alpha reductase converts testosterone to dihydrotestosterone which has been shown to be responsible for the initial development and subsequent enlargement of the prostate gland.  Hence, by inhibiting this enzyme, a reduction in dihydrotestosterone is observed.
• It is currently indicated for 
• the treatment of symptomatic benign prostatic hyperplasia in men with an enlarge prostate as monotherapy and in combination with tamsulosin (an alpha blocker)
• Just a side note: the advisory committee comprised of experts who looked at the data submitted to the FDA to make recommendation.  The final decision as to whether the drugs get approved lays solely on the FDA.  However, most of the time, the FDA often respects recommendations from the advisory committee.  With that said, the chance of dutasteride being approved by the FDA is slim. 
• A set back for GSK and Valeant's ezogabine is announced on December 1, 2010.  The FDA issued a complete response stating it is unable to approve ezogabine as the adjunctive treatment for partial-onset seizures in adults.
• GSK and Valeant announced that they will work to provide a timely response to the FDA as soon as possible in 2011.  
• No specific information is provided as to what both companies need to do in order to gain approval.  GSK reported that the reasons were non-clinical.

Axcan Acquired Eurand for $583 M

Axcan acquired Eurand for an approximately $583 M.

Eurand and Axcan entered into a definitive agreement on December 1, 2010.  Under the agreement, Axcan agreed to acquire Eurand for $12 per share in cash.

Axcan is a privately-held company that focused on the development and treatment of gastrointestinal diseases and disorders.  It has products marketed in many different countries across the world.

in the US, Axcan is currently marketing the following products

• AquaDeks
• Bentyl
• Canasa / Canasa PAC
• Carafate
• Flutter
• Photofrin
• Pylera
• Scandical
• Scandishake
• Ultrase / Ultrase MT
• URSO Forte Scored / URSO 250
• Viokase

Eurand currently has the following products in the market:

•  Zenpep
• SourceCF
• Both are used in cystic fibrosis patients

PS: correction from previous post: Axcan was exchanged for Eurand.

APP Pharmaceutical to launch topotecan after receiving FDA approval

APP Pharmaceuticals plans to launch Topotecan for injection immediately upon receiving approval from the FDA.

About Topotecan
Topotecan is a topoisomerase I inhibitor which works to inhibit topoisomerase I.  By inhibiting topoisomerase I, topotecan exerts its cytotoxic effects causing DNA breakage which leads to cell death.

Current Marketed Products:
Topotecan is currently marketed as Hycamtin by GSK.  Hycamtin is available in two formulations: powder for injection and capsules.

• Powder for Injection:  4 mg (in 4 ml vial, preservative free)
• Capsules: 0.25 mg (available in bottles of 10)

APP's Product:
APP's Topotecan comes in only one formulation: injection.

• APP's topotecan will be marketed in a preservative-free containing 4 mg of topotecan.

Indications:
Topotecan is indicated for

• the treatment of small cell lung cancer sensitive disease after patients have failed first line therapy (which was cisplain + etoposide)
• use in combination with Cisplatin for stage IV-B in patients with small cell lung cancer
• the treatment of recurrent or persistent carcinoma of the cervix when surgery and/or radiation therapy are not curative.

Blackbox Warning

•  Topotecan cannot be used in patients whose neutrophil counts are less than 1,500 cells/mm3.  Peripheral blood counts should be monitored frequently in patients receiving topotecan in order to assess the occurrence of bone marrow suppression, primarily neutropenia.

Other information:

• Small-lung cancer composed a small portion of patients who are diagnosed with lung cancer.
• Small Lung Cancer is often characterized as being an aggressive form of lung cancer when the cells are fast-producing.  However, this makes them more susceptible to chemotherapy agents.
• With first line agents are cisplatin and etoposide, many patients will only new one or two rounds of chemotherapy.  Although a high percentage of patients achieves good responses, many often relapse.  Once relapsed, depending on how long ago they received the first line chemotherapy, topotecan is then indicated.
•  APP Pharmaceutical is a subsidiary of Fresenius Kabi AG (it was acquired on September 10, 2008).  Fresenius Kabi AG is a subsidiary of Fresenius SE.

My Comments:

• APP's entry into this market might increase its revenue a little bit. Unless they significantly lower its drug's cost to make the market share, they might not be a big threat to the current marketed products.  It is worth to note that APP's topotecan is the first generic of Hycamtin.  Hycamtin was approved originally in 1996.  So it has been around for more than 20 years.  In the past 20 years, no other generic has entered the US.  This might say either the market is small or not too profitable for other companies to come in. However, with proper marketing methods and good pricing, APP might be able to enter and share GSK's market.  As mentioned, Hycamtin(R) sale was 157.1 M in the US (not quite a lot compared to other cancer drug).  So I wouldn't expect APP's will generate a lot of revenue based on this single entry and GSK's profit might not be hurt extremely bad based on this.

NDA submission for Hematide of Affymax and Takeda is confirmed

Affymax and Takeda have decided to move forward with the development of peginesatide or Hematide for the treatment of anemia in chronic renal failure patients who are on dialysis in the US after the pre-New Drug Application meeting with the FDA.  The company plans to submite the NDA to the US FDA by the second quarter 2011.

• About Hematide
• Hematide or peginesatide is a synthetic dimeric peptide-based erythropoietin stimulating agent (ESA). It is pegylated with polyethylene glycol.  What this means is: it s a dipeptide that is attached to polyethylene glycol which acts to increase its half life (see glossary for information) and its stability.  ESA works to increase the production of red blood cell in the bone marrow.   Normally, erythropoietin is synthesized and secreted from the kidney.  Patients with renal disease and are on dialysis have dysfunctional kidneys.  Hence, the ability to synthesize and secrete erythropoietin is limited.  This leads to the decrease in production of red blood cell.  As a result patients often become anemic and are put on different drug regimens to manage anemia.  ESA works to mimic the action of erythropoietin to the erythropoietin receptors in the bone marrow in order to increase the production of red blood cells.
• Hematide will be given as subcutaneous injection
• Collaboration
• In 2006, Affymax and Takeda entered into a development and commercialization colloboration of Hematide.  The collaboration was expanded into a worldwide agreement within the same year.  Under the agreement, Affymax is responsible for the development and commercialization of Hematide for renal indications in the US.  In a mean time,

Companies (Thomson and Cardinal Health) contribute to CyberMonday with Acquistions of GeneCo and Yong Yu respectively

It's CyberMonday so a couple of companies have demonstrated their buying power...

• On November 29 2010, Thomson Reuters announced that it has acquired GeneGo for an undisclosed amount.
• GeneGo has its headquarter in San Diego, CA and offices in Moscow and Michigan.  GeneGo is a "provider of biology and disease information, analytics, and decision support solutions for pharmaceutical research and development".  The addition of GeneGo capabilities will expand Thomson's ability offer to its customer in defining different disease etiologies and potential targets for therapies. 
• On the same date, Cardinal Health announced that it has acquired a privately held Zuellig Pharma China with a $470 M USD.  Zuellig Pharma China is a health care distributor and also the largest pharmaceutical important in China.  It's known locally as Yong Yu.
• YY was established in 1993. Its annual sale has crossed over $1B.  China is an emerging health care markets.  YY has extensive network within China through its wholesalers as well as direct-to-customer distribution center network.  Its products are distributed in 49K hospitals and more than 123K pharmacies in China.  With this addition, Cardinal Health takes a step closer to enter the emerging/booming Chinese Health Care market.  Although major cities have become industrialized, other smaller cities are still in development.  The need for medication will continue to increase.  With over 1.3 B people living in China, this is many times more than the number of people living in the US.  However, here is a word of caution, Chinese market has great potential.  But health care needs to be accessible which means affordable.  So the result is still to be seen. 

The primary endpoind of the phase III trial using isavuconazole has been changed

Basilea and Astellas have agreed to change the primary endpoint of its phase III trial using isavuconazole for the treatment of invasive aspergillosis with the FDA.  All-cause mortality, initially a secondary endpoint, now becomes the primary endpoint.  Previously the primary endpoint, overall response, has now become a secondary endpoint. According to Basilea, the change will not impact the phase III trial's time line.  The trial is expected to be complete by the end of 2010 or early 2011.  Results are expected in 2013. (Note comment below)

• Isavuconazole is a novel, water-soluble, broad-spectrum  antifungal medication developed by Basilea.  It can be given intravenously or orally in capsule.  It has fast track designation in the US. 
•  It's currently in multiple clinical trials for different indications: treatments of yeast infections (candidemia/invasive Candida infections), mold infections (invasive aspergillosis), and rare molds and aspergillosis in renally impaired patients.

• Astellas and Basilea entered into a worldwide (including Japan) license, co-development and co-promotion agreement with Basilea Pharmaceutica International in Feb 2010.  Under the agreement, Astellas has exclusive rights to develop and commercialize isavuconazole in the stated territory.  Basilea has options to co-promote the product in the US, Canada, major EU countries and China.  An upfront payment of 75 M was made to Basilea.  Up to 478 M could be made to Basilea based on certain pre-specified development and sales milestones.  Other royalties will also be made to Basilea. 
• In addition, Astellas will head the development and is responsible for the major funding needed to complete clinical development of isavuconazole.  Basilea will initially manufacture isavuconazole.  Astellas has the right to manufacture the product.
• Invasive Aspergillosis is commonly seen in patients with transplant patients, patients with reduced or decreased immune system (eg. AIDS) and others.  
• Current treatment (not inclusive) includes:  
• Anti-fungal (the azole)
• voriconazole: main in its group (first line treatment)
• itraconazole
• posaconazole
• ravuconazole
• Amphotericin B (different formulations)
• liposomal amphotericin B
• amphotericin B colloidal dispersion
• amphotericin B lipid complex
• Echinocandins
• caspofungin: when the organism does not respond to others
• micafungin
• anidulafungin
• 5-flucytosine

• Comment:I find it interesting that the FDA and the companies agree to change the primary endpoint to all-cause mortality.  All-cause mortality means all deaths regardless of causes need to be accounted for.   Usually, all-cause mortality is not often treated as primary endpoint.  In this case, the phase III trial is designed to show that isavuconazole is non-inferior to current first line treatment which is voriconazole. Patients in the study population are not the healthiest. In addition, the invasive Aspergillosis is rapidly spreading as well as having higher mortality rate than others.  By changing it to all-cause mortality, the study now needs to show that the medication is actually saving life instead of just improving clinical symptoms.  I don't think it will affect the outcome as much but it might give insight to as whether the drug is worth for hospital to adopt if it gets approved down the line based on the available data.

GlaxoSmithKline formed alliance with Binnopharm to perform secondary manufacture for its vaccine in Russia

GlaxoSmithKline formed vaccine production alliance with Binnopharm in Russia. 
The alliance will allow Binnopharm to provide secondary manufacture a number of GSK vaccine in Russia.  GSK will provide BinnoPharm bulk vaccine as well as technology and expertise.  Binnopharm will perform filling and packaging a number of GSK vaccines in agreement with current Good Manufacturing Practice (cGMP)
 standards.

• Binnopharm is a biotechnology and pharmaceutical manufacturing company.  It is capable of producing tablet, capsules, ampules, sprays, and aerosols.  It's based on Moscow, Zelenograd.  The company belongs to JFC Sistema.   BinnoPharm also has a distribution subsidiary, Phyta Line.  Phyta Line is one of the largest wholesalers of active pharmaceutical ingredients in Russia.
• In 2009, BinnoPharm had 55.7 M in revenus and 165 M in assets (US dollar)