The Pharmaceutical Litigation Blog™

Natco Pharma is planning to relaunch the controversial nanotechnology-based breast cancer treatment Albupax in India following the Union health minister staying DCGI’s order prohibiting the sale of the drug, reports said.

Natco’s Albupax, which is claimed to be the generic equivalent of Abraxane developed by US-based Abraxis Biosciences, has been directed to be taken off from Indian markets after an analysis of the drug in the government’s Kolkata-based Central Drug Laboratory (CDL) found that it contained high levels of endotoxin, a harmful substance.

Natco has questioned the authenticity of CDL’s report pointing out that the government lab’s analysis may not be fool-proof as it lacked the sophisticated modalities required for the testing of highly complex nanotech drugs like Albupax.

Natco Pharma recalled Albupax from the market as DCGI had asked Natco to withdraw the drug within two weeks, after tests showed the endotoxins in the drug could cause damage to the liver.

However, Natco approached the health ministry alleging that the DCGI’s decision based on the CDL parameters as unfair.

The Union health ministry, then, issued a stay order on DCGI directive to pull back the drug from market.

The ministry has directed more tests on Albupax and if these tests proved the drug to be safe  Natco can relaunch the product, reports said quoting health ministry officials.

Natco launched Albupax in Indian market in September 2008 at a price which nearly Rs 5000 less per vial than the retail selling price of Abraxis Abraxane which is marketed in India by the Bangalore-based Biocon Ltd.

Abraxis, in complaint letter to DCGI filed in early 2009 pointed out that Natco’s Albupax can lead to serious side-effects.

Following Abraxis complaint DCGI ordered a fresh round of laboratory anlysis for Albupax.

Examination of Albupax samples at the Kolkata-based Central Drug Laboratory (CDL) found that the breat cancer nanotech drug had high levels of endotoxins and chloroform.

DCGI immediately ordered recall of Albupax from the market, based on the CDL test report.

However, Natco Pharma, which recalled the drug following the DCGI directive, said test results on endotoxin levels are highly dependent on the test kit employed due to interference caused by the nano particulates and excipient proteins.

The kit by M/S Charles River is employed by the Govt. analyst CDL, Kolkata and the results obtained by this kit are known to vary by as much as 2-to-four fold according to manufacturer’s own manual, Natco explained in a press note.

The samples when analysed by a different kit (viz., the Lonza’s kit) yield different results all within the specified limits for endotoxins. These results are further confirmed by the National Accreditation Board for testing and calibration for Laboratories (NABL) accredited laboratory. Natco  obtained product license for Albupax  using the Lonza’s kit.

Natco has realized these test kit dependent results and is in the process of streamlining the test procedures to achieve foolproof results as a proactive measure.

A complex topic like nano technology and the test methods are being debated in the press without providing any technical background and details.

Abraxane, which contains paclitaxel protein-bound particles for injectable suspension (albumin bound), is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Abraxane is a formulation of paclitaxel with a mean particle size of approximately 130 nanometers, that uses the natural properties of a human protein, albumin, to deliver the drug more effectively to tumors. By wrapping the albumin around the active drug. Abraxane can be administered to patients at higher doses, resulting in higher concentrations of the drug at the tumor site and higher efficacy compared to solvent-based paclitaxel.

Clinical trials have demonstrated that the tumor response rate was nearly double for patients who received Abraxane compared to those who received solvent-based paclitaxel.

US Food and Drug Administration approved Abraxane in 2005 and the European Medicines Agency (EMEA) approved Abraxane in 2008.

Abraxane is currently in various stages of investigation for the treatment of the following cancers: first-line metastatic breast, non-small cell lung, melanoma, pancreatic and ovarian.

Apart from Natco Pharma, Fresenius Kabi Oncology, (formerly Dabur Pharma) is another firm which launched a generic version of Abraxane. Dabur Pharma launched the drug in the brand name Nanoxel in India in January 2007.

Abraxis’ Abraxane is marketed by Bangalore-based Biocon Ltd in India.

Abraxis’ claim for a patent for Abraxane in India was rejected following pre-grant opposition filed by Natco.

Abraxis then appealed to the Delhi high court. The high court has directed Abraxis to approach the Intellectual Property Appelate Board to settle the dispute.

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DP-b99, an experimental medicine to control neurological damages caused by stroke, may reach the market earlier than expected –in 3 to 4 years’ time, reports said quoting D-Pharm’s senior officials.

Trial data of DP-b99 analyzed has found that the drug has doubled the number of patients who completely recovered from strokes caused by blood clots.

If the final phase of clinical trial, which the drug is currently undergoing, could repeat the positive outcome,the U.S. Food and Drug Administration may relax D-Pharm from conducting another trial with the drug to establish the findings.

DP-b99 seeks to address an array of brain damaging processes occurring in stroke patients. The drug uses D-Pharm’s proprietary Membrane Activated Chelator (MAC) platform technology.

D-Pharm completed testing of DP-b99 in pre-clinical and then in Phase I and Phase II clinical studies.

In a Phase IIb trial in 150 ischemic stroke patients, DP-b99 increased by two-fold the percentage of patients that completely recovered from ischemic stroke. DP-b99 may be administered within a nine hour therapeutic window.

In December 2009, D-Pharm Ltd started enrollment of patients with acute ischemic stroke into its Phase III clinical study of DP-b99 (MACSI).

The MACSI trial involves numerous medical centers in the US, Canada, Europe, Israel, South Africa, South Korea and Brazil. DP-b99 is D-Pharm’s most advanced product developed for protection of brain cells suffering from restricted blood and oxygen supply (ischemia).

The MACSI study is as international, multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial. The trial will compare the stroke outcome in a group of patients treated with placebo (an inactive substance) to patients treated with 1 mg/kg/day of DP-b99 for 4 consecutive days.  The study is expected to enroll, in total, 770 patients at 120 – 140 clinical sites worldwide.

For the global development of DP-b99, D-Pharm Ltd. will collaborate with its partners Yungjin Pharmaceuticals in S. Korea and Wanbang Biopharmaceuticals in China.

Stroke is a leading cause of serious long-term disability and the second most common cause of death worldwide. The number of acute ischemic stroke patients in the US, Western Europe and Japan is around 1.5 million; including the territories of S. Korea and China may almost double this figure.

Stroke accounts for 5.7 million deaths annually, Worldwide, according to the World Stroke Organization.

Nearly 795,000 people suffer a new or recurrent stroke each year in the U.S alone, according to the American Stroke Association.
D-Pharm is a clinical stage, biopharmaceutical company pioneering the development of lipid-like therapeutics and has generated a rich pipeline of patent protected proprietary products.

D-Pharm’s pipeline includes advanced clinical stage products DP-b99 for treatment of acute ischemic stroke patients and DP-VPA, a novel drug for treatment of epilepsy, bipolar disorder and prophylaxis of migraine.

DP-460 is in preclinical development intended as an oral, disease-modifying therapy for Alzheimer’s disease. Other mimics of bioactive lipids, LipidoMimetix, are at an earlier developmental stage, for cancer.

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The Serum Institute of India (SII), India’s largest vaccine maker, has announced the commencement of the last crucial phases of human trials of its swine flu vaccine Fluvac.

The Serum Institute of India has received the approval from the Drug Controller-General of India (DCGA), recently, reports said.

The phase 2 and 3 trials of Serum’s intranasal vaccine will be conducted in 330 patients at 10 hospitals in Pune, Ahmedabad, Kolkata, Chennai, Indore, Lucknow, Ludhiana and Bangalore.

The studies will be completed in three months.

Ahmedabad-based Zydus Cadila is the first Indian company that started phase 2 & 3 studies of H1N1 vaccine in India.

India may start H1N1 vaccination drive against swine flu in the coming weeks as the bridge clinical trials to ascertain safety of the imported vaccine samples from Sanofi Pasteur is completed and the data submitted for regulatory review.

Indian Government has imported 1.5 million doses of vaccines from Sanofi Pasteur, the vaccines division of Sanofi Aventis Group

The imported H1N1 vaccines from Sanofi-Pasteur will be mainly used for the high-risk group of medical practitioners.

Sanofi-Pasteur’s H1N1 vaccine will cost around Rs.300 per dose in India.

The India-made H1N1 swine flu vaccines will not be available before April.

Initially, India was planning to import four million doses of the vaccine. Indian manufacturers will now supply the remaining doses.

However, the health ministry cut it down to 1.5 million doses, in view of the possibility indigenously produced H1N1 swine flu vaccine to be made available by March.

The health ministry has been trying to make the vaccine available in India for the last three months and had sped up regulatory approvals for studies to be conducted on the safety of the vaccine.

India’s ministry of health and family welfare was holding discussions with indigenous vaccine manufacturers to assess their capacity to develop, manufacture and supply H1N1 swineflu vaccine for national programme.

Panacea Biotec has entered into an advance marketing agreement with Ministry of Health and Family Welfare (MoHWF) for supplying its H1N1 swine flu vaccine Pandyflu.

Panacea Biotec, which is based in New Delhi, northern India, is currently doing clinical studies on Pandyflu vaccine. Pandyflu is an inactivated split version vaccine using egg- based technology.

Apart from Zydus Cadila and Serum Institute, Bharat Biotech has also launched studies for cell culture vaccine HN-Vac against H1N1 influenza swine flu in India.

Bharat Biotech, Panacea Biotec and Serum Institute of India are the three biotech companies assigned by the Indian government to develop H1N1 swine flu vaccine.

Recently, India’s Biological E Limited has entered into an agreement with USA’s VaxInnate Corporation to license its recombinant H1N1 pandemic swine flu vaccine.

Cadila Pharmaceuticals, another pharma major from Ahmedabad, is also developing an H1N1 Swine flu vaccine in callaboration with Novavax.

The H1N1 vaccine could get cheaper in India as more such indigenous vaccines come to the market late this year.

Similarly, Drug Controller General of India has given approval for Panacea Biotec to conduct clinical trials for its swine flu vaccines in the country, recently.

India has reported 1376 deaths from H1N1 swine flu infection in the country as of 2nd March 2010, according to an official communique from the ministry of health and family welfare issued by Press Information Bureau.

India has tested samples from 128944 persons for Influenza A H1N1 in government laboratories and a few private laboratories across the country till date and 29710 or 23.04% of them have been reported positive.

The western state of Maharashtra comes first with 369 deaths among the total 5577 lab confirmed cases of H1N1 swine flu deaths.

Maharashtra is followed by other states – Gujarat and Rajasthan -in the western region with 289 and 194 deaths respectively.

Gujarat and Rajathan have 1214 and 2192 each.

Delhi has the highest number of lab confirmed cases of H1n1 infection: 9687. However, India’s capital city registered only 95 cumulative number of deaths from swine flu.

Among the southern states, Karnataka accounted for the highest casualties with 148  deaths and 2138 cases of lab confirmed infections.

Andhra Pradesh reported 52 deaths and 782 infections while the states of Tamil Nadu and Kerala registered 7 deaths 2084 confirmed infections and 37 deaths and 1468 infections respectively.

The north-eastern states of West Bengal, Manipur, Meghalaya, Nagaland and nothern states of Bihar, Jharkhand as well as union territories Daman Diu, Andaman Nicobar reported zero deaths from swine flu.

It was reported earlier that H1N1 influenza or swine flu infections could continue in India for one more year.

Even though the trend in H1N1 swine flu infection is on the decline globally, it has now started showing up in places which are new. So, naturally India may have to face another year of swine flu infection, according to V M Katoch, Director General, Indian Council of Medical Research (ICMR).

World Health Organisation recently reported that there is still intensive virus activity in some countries including India, even though H1N1 swine flu started waning in other parts of the world including US and Europe.

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Fruitflow, a tomato-extract product developed by Provexis, has been found effective to prevent blood clots that risk heart attacka nd strokes without the side-effects of the widely used blood thinner Aspirin.

Fruitflow is a water-soluble tomato concentrate.

Clinical studies using Fruitflow that compared the effects on platelet aggregation of the tomato-extract product and aspirin showed that up to 30 percent reduction from baseline platelet aggregation.

Platelet aggregation can contribute to unwanted clot formation in the bloodstream.

The seven-months long human studies also examined the interactions between Fruitflow and aspirin consumed together.

Aspirin could lead to gastric ulceration and bleeding.

The effect takes place within three hours of consumption and lasts for up to eighteen hours, making it ideal for daily dosage in functional foods or dietary supplements.

Provexis has developed a syrup format for use in food & beverages and a concentrated powder format for tablets and capsules.

Fruitflow syrup is GRAS (Generally Regarded as Safe) by the US FDA and is not regarded as a Novel Food in the EU, clearing it for wide use in foods, beverages and supplements.

In May 2009, the Fruitflow technology was the first to be substantiated by the European Food Safety Authority (EFSA) under the new Article 13(5) for proprietary and emerging science.

In December 2009 the European Commission authorised the health claim “Helps maintain normal platelet aggregation, which contributes to healthy blood flow”, which was the first wording to be authorised under Article 13(5).

The technology has been granted patents in the EU, US, Australia, Canada and Mexico, with Japan pending. Further patents have been filed for the bioactive components of Fruitflow and for other developmental areas such as deep vein thrombosis and triglyceride lowering.

Discovered by Professor Asim Dutta Roy at the Rowett Institute in 1999, the technology has been developed by the Provexis team in recent years. This development programme includes eight clinical trials.

The product is commercially-ready for delivery in a wide range of food, beverage and dietary supplement formats.

In February, Provexis entered into a long-term alliance agreement with DSM Nutritional Products for exclusive global rights to Fruitflow.DSM Nutritional is a leading supplier of vitamins, carotenoids and other fine chemicals to the feed, food, pharmaceutical and personal care industries.

This Agreement will provide for a partnership and structure in which DSM and Provexis will develop, market and sell Fruitflow as an ingredient in all formats and territories.

Profits from the Agreement will be shared by the parties on an agreed basis, linked to various performance milestones.

Provexis will continue to support the development of current and future formats of Fruitflow and DSM will contribute with its manufacturing and selling experience and excellence to a successful commercialisation of Fruitflow.

Future claim areas under development include deep vein thrombosis, metabolic syndrome and type-II diabetes.

Provexis is focused on the discovery, development and licensing of technologies for the functional food, dietary supplement and medical food sectors.

The company was originally spun out of the Rowett Institute (now part of the University of Aberdeen) in 1999 to commercialise their tomato extract discovery using venture capital funding. Provexis Limited was reversed into Nutrinnovator in 2005 and its major investors are DSM Venturing and Rising Stars Growth Fund (part of Enterprise Ventures).

The company has additional biotechnology developments, including a joint venture with the University of Liverpool to develop an extract of plantain which aids the treatment of inflammatory bowel disease, and an early stage technology under option from University of Manchester for the prevention and treatment of peptic ulcers.

DSM Nutritional Products is the world’s leading supplier of vitamins, carotenoids and other fine chemicals to the feed, food, pharmaceutical and personal care industries. The business has sales of about EUR 2 billion and a long tradition as a pioneer in the discovery of new products, new formulations and attractive applications for all industry segments

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Hizentra, a 20 percent concentration of human immunoglobulin to be administered subcutaneously for treating patients diagnosed with primary immunodeficiency (PI), has been granted approval in US.

Once weekly immunoglobulin (Ig) replacement therapy, Hizentra provides effective protection against infection by maintaining a steady and normal level of immunoglobulin in the body, announced the developer of the drug CSL Behring in a press release.

Hizentra is claimed to be the first 20 percent subcutaneous immunoglobulin (SCIg) approved in the U.S.

Hizentra is derived from human plasma.This high-concentration immunoglobulin is stabilized with L-proline, a naturally-occurring amino acid.

L-proline allows Hizentra to be stored at room temperature (up to 25°C [77°F]). Because no refrigeration is necessary, Hizentra is ready to use, offering patients and physicians convenience and portability,

“As the first SCIg treatment with a 20 percent concentration of immunoglobulin, Hizentra represents an effective, convenient choice of at-home Ig therapy that will allow people with PI to schedule treatment around their busy lives instead of scheduling their lives around treatment,” stated Robert Lefebvre, vice president and general manager, U.S. Commercial Operations at CSL Behring.

For patients with primary immunodeficiencies, immunoglobulin replacement therapy with a product like Hizentra can help treat existing or chronic infections and prevent new infections from occurring.

Immunoglobulin, or Ig, is a blood component that has become standard immune replacement therapy for most people living with PI, and nearly 70 percent of PI patients receive Ig replacement therapy.

Since the 1980s, the first-line therapy for most primary immunodeficiencies patients has been intravenous immunoglobulin (IVIg), in which immunoglobulin is delivered through a needle into the vein.

No single treatment works for every type of PI, but infusions of replacement antibodies (immunoglobulins) can help supplement the immune system to prevent infection in nearly three-quarters of primary immunodeficiencies cases that are due to antibody deficiencies.

Many patients, however, cannot easily tolerate intravenous infusions due to serious side effects or poor veins.

Hizentra has a small, portable pump to self-administer weekly infusions by injection under the skin (subcutaneous administration).

Hizentra is part of CSL Behring’s Ig franchise, which also includes both the first FDA-approved subcutaneous Ig treatment and the first proline-stabilized IVIg therapy.

Hizentra will be manufactured at CSL Behring’s new state-of-the-art facility, located at its center of excellence for immunoglobulins in Bern, Switzerland.

What is primary immunodeficiency?

Primary immunodeficiencies are a group of disorders, usually genetic, that cause a malfunction in all or part of the immune system, thereby rendering the patient unable to fight off infections caused by everyday germs.

Nearly 100 types of primary immunodeficiencies exist. For individuals with primary immunodeficiencies, many of them children, infections may not improve as expected with usual treatments and may keep returning.

As a result, patients may face repeated rounds of antibiotics or hospitalization for treatment. Repeated infections can lead to organ damage, which over time can become life-threatening. Some infections, such as meningitis, may even result in death.

Primary immunodeficiencies affect an estimated 10 million people worldwide, and the incidence is estimated to be 1 in 10,000.

Due to the X-linked inheritance in many primary immunodeficiencies syndromes, more males are affected than females.

CSL Behring is a subsidiary of CSL Limited, a biopharmaceutical company headquartered in Melbourne, Australia.

CSL Behring is a leader in the plasma protein therapeutics industry. The company manufactures and markets a range of plasma-derived and recombinant therapies worldwide.

CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies and inherited respiratory disease.

The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in newborns.

CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma.

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India may start H1N1 vaccination drive against swine flu in the coming weeks as the bridge clinical trials to ascertain safety of the imported vaccine samples from Sanofi Pasteur is completed and the data submitted for regulatory review.

Indian Government has imported 1.5 million doses of vaccines from Sanofi Pasteur, the vaccines division of Sanofi Aventis Group

The safety study of Sanofi Pasteur’s H1N1 vaccine doses have been conducted 100 people at two sites –Kalavati Saran Hospital in Delhi and Bharatiya Vidyapith in Pune, reports said.

Drug Controller General of India will review the trial data and will allow the Sanofi Pasteur vaccine for immunization purpose in the country.

The imported H1N1 vaccines from Sanofi-Pasteur will be mainly used for the high-risk group of medical practitioners.

Sanofi-Pasteur’s H1N1 vaccine will cost around Rs.300 per dose in India.

The India-made H1N1 swine flu vaccines will not be available before April.

Initially, India was planning to import four million doses of the vaccine. Indian manufacturers will now supply the remaining doses.

However, the health ministry cut it down to 1.5 million doses, in view of the possibility indigenously produced H1N1 swine flu vaccine to be made available by March.

The health ministry has been trying to make the vaccine available in India for the last three months and had sped up regulatory approvals for studies to be conducted on the safety of the vaccine.

India’s ministry of health and family welfare was holding discussions with indigenous vaccine manufacturers to assess their capacity to develop, manufacture and supply H1N1 swineflu vaccine for national programme.

Panacea Biotec has entered into an advance marketing agreement with Ministry of Health and Family Welfare (MoHWF) for supplying its H1N1 swine flu vaccine Pandyflu.

Panacea Biotec, which is based in New Delhi, northern India, is currently doing clinical studies on Pandyflu vaccine. Pandyflu is an inactivated split version vaccine using egg- based technology.

Zydus Cadila was the first Indian company to file the clinical trial protocol with the DCGI pushing back other domestic rivals who are also in race to launch H1N1 swine flu vaccine in India.

Zydus Cadila would have the vaccine ready by March, so the government would not need to import batches, according to government sources.

Serum Institute of India has  also been granted approval by the Drug Controller General of India (DCGI) to carry out clinical studies for the intra-nasal spray vaccine.

And most recently, Bharat Biotech, one of India’s leading vaccine makers, has launched first-in-man studies for cell culture vaccine HN-Vac against H1N1 influenza swine flu in India.

Bharat Biotech, Panacea Biotec and Serum Institute of India are the three biotech companies assigned by the Indian government to develop H1N1 swine flu vaccine.

Recently, India’s Biological E Limited has entered into an agreement with USA’s VaxInnate Corporation to license its recombinant H1N1 pandemic swine flu vaccine.

Cadila Pharmaceuticals, another pharma major from Ahmedabad, is also developing an H1N1 Swine flu vaccine in callaboration with Novavax.
CPL Biologicals Pvt. Ltd, the newly formed joint venture between Cadila Pharmaceuticals in India, expects to start producing H1N1 swine flu vaccine in next four months, Novavax Inc announced in a press release.

The H1N1 vaccine could get cheaper in India as more such indigenous vaccines come to the market late this year.

Similarly, Drug Controller General of India has given approval for Panacea Biotec to conduct clinical trials for its swine flu vaccines in the country, recently.

India has reported 1376 deaths from H1N1 swine flu infection in the country as of 2nd March 2010, according to an official communique from the ministry of health and family welfare issued by Press Information Bureau.

India has tested samples from 128944 persons for Influenza A H1N1 in government laboratories and a few private laboratories across the country till date and 29710 or 23.04% of them have been reported positive.

The western state of Maharashtra comes first with 369 deaths among the total 5577 lab confirmed cases of H1N1 swine flu deaths.

Maharashtra is followed by other states – Gujarat and Rajasthan -in the western region with 289 and 194 deaths respectively.

Gujarat and Rajathan have 1214 and 2192 each.

Delhi has the highest number of lab confirmed cases of H1n1 infection: 9687. However, India’s capital city registered only 95 cumulative number of deaths from swine flu.

Among the southern states, Karnataka accounted for the highest casualties with 148  deaths and 2138 cases of lab confirmed infections.

Andhra Pradesh reported 52 deaths and 782 infections while the states of Tamil Nadu and Kerala registered 7 deaths 2084 confirmed infections and 37 deaths and 1468 infections respectively.

The north-eastern states of West Bengal, Manipur, Meghalaya, Nagaland and nothern states of Bihar, Jharkhand as well as union territories Daman Diu, Andaman Nicobar reported zero deaths from swine flu.

It was reported earlier that H1N1 influenza or swine flu infections could continue in India for one more year.

Even though the trend in H1N1 swine flu infection is on the decline globally, it has now started showing up in places which are new. So, naturally India may have to face another year of swine flu infection, according to V M Katoch, Director General, Indian Council of Medical Research (ICMR).

“In places where swine flu cases were already reported, it has been contained. But we found that it is spreading to new pockets and hence we face the challenge for one more year. It is like a flood and will take some time to recede,” V M Katoch stated.

World Health Organisation recently reported that there is still intensive virus activity in some countries including India, even though H1N1 swine flu started waning in other parts of the world including US and Europe.

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Otelixizumab, an experimental drug which could offer a potential eight-day course of daily intravenous infusions reducing the amount of insulin they need to inject on a daily basis to control blood sugar in type 1 diabetes patients, is currently in human studies.

Otelixizumab may help preserve patients’ natural ability to produce insulin for years in type 1 diabetes, according to Tolerx Inc, the developer of the drug.

Otelixizumab, a target T cell immunomodulator, is a monoclonal antibody that binds to CD3, a T lymphocyte receptor involved in normal cell signaling.

Otelixizumab is thought to work by blocking the function of T effector cells that attack the body’s tissues and cause autoimmune disease while inducing a subset of T cells known as T regulatory cells. It is thought that the T regulatory cells may protect against T effector cell damage well after the drug has been eliminated from the body.

Otelixizumab (TRX4) is under development in collaboration with GlaxoSmithKline (GSK) for the treatment of autoimmune new-onset type 1 diabetes, with the potential to be developed in other indications, such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease.

In a study involving patients with new-onset type 1 diabetes otelixizumab helped preserve the function of insulin-producing beta cells in the pancreas, and reduced the amount of insulin needed to control blood glucose levels, for 18 months after only 6 days of otelixizumab administration.

This multicenter study included 80 subjects newly diagnosed with type 1 diabetes. New-onset type 1 diabetes subjects had been treated with insulin for less than four weeks and were randomly assigned to receive either otelixizumab or placebo for 6 consecutive days.

No additional courses of otelixizumab were administered. During the 18 months following treatment, subjects reported how much insulin they took.

The amount of natural insulin produced by the subjects’ beta cells was assessed by measuring c-peptide, a protein that is always produced along with insulin.

At 6, 12, and 18 months, beta cell function was maintained better in otelixizumab-treated subjects than in placebo-treated subjects.

In addition to 18 months of follow-up, there was a significant decrease in insulin use at 24, 36, and 48 months of follow-up as compared with placebo. Subjects who received otelixizumab produced more c-peptide than the placebo group, meaning that their beta cells were producing more natural insulin. Otelixizumab did have some side effects.

During the 6 days of otelixizumab administration, especially on the first day, subjects had headaches, nausea, body aches, and other flu-like symptoms.

A few weeks later, subjects had a flare-up of a virus called EBV, the same virus that causes mononucleosis. Most subjects had symptoms such as sore throat and swollen glands. All of these symptoms were temporary and most were mild.

Tolerx is conducting a Phase 3 study called DEFEND-1 as well as a Phase 2 study — called TTEDD — of otelixizumab in subjects with type 1 diabetes.

TTEDD is an ongoing dose-ranging and safety study in subjects with new-onset or established type 1 diabetes that have detectable beta cell function, as measured by c-peptide at study entry. The primary objective of TTEDD is to explore multiple dosing regimens of otelixizumab.

Tolerx has completed enrolling subjects in a multi-national Phase 3 study, DEFEND-1.  The DEFEND-1 study is investigating the ability of otelixizumab to preserve beta cell function, which may reduce the risk of both short- and long-term complications of the disease.

Patients will be monitored during the 12-month follow-up period and c-peptide levels (a surrogate measure of beta cell function) will be measured as the primary endpoint. Secondary endpoints will evaluate the patient’s ability to maintain excellent glycemic control as measured by HbA1c levels and the amount of daily injected insulin required.

Tolerx plans to conduct a second confirmatory Phase 3 study of otelixizumab in new-onset autoimmune type 1 diabetes, entitled DEFEND-2.

Otelixizumab is also being tested in moderate-to-severe psoriasis, multiple dosing studies in type 1 diabetes, and may initiate additional clinical studies with GSK in patients with other autoimmune diseases, Tolerx stated.

What is type 1 diabetes?

Approximate 20.8 million people in the U.S. have diabetes, of which 5%-10% have type 1 diabetes, according to the Centers for Disease Control and Prevention (CDC).

In the U.S., 36,000 new patients are diagnosed each year, including over 15,000 children.

Type 1 diabetes is an autoimmune disease in which the body’s immune system attacks and destroys the insulin-producing cells (the beta cells) of the pancreas.

Current treatment for type 1 diabetes consists of managing blood glucose levels through diet, exercise, and injections of insulin.

While this approach can be effective, it does not affect the underlying cause of the disease, which is the loss of beta cell function resulting from an autoimmune attack.

Some natural insulin production in those with type 1 diabetes results in better metabolic control, and may reduce the risk of the long-term effects of the disease (such as serious eye disease, cardiovascular disease, and nervous system, kidney, and vascular disorders), and may reduce the need for administered insulin.

Headquartered in Cambridge, MA USA.Tolerx, Inc is developing novel therapies intended to treat autoimmune diseases, diabetes, and cancer by specifically modulating T-cell activity.

The company’s pipeline includes MTRX1011A, an anti-CD4 antibody that is being developed in collaboration with Genentech, Inc. for the treatment of autoimmune indications; and two pre-clinical candidates, TRX518 and TRX385, that enhance immune responses and are being evaluated for potential benefit in the treatment of cancer, chronic viral diseases, and as vaccine adjuvants, besides its lead candidate, otelixizumab.

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Clinical studies of ocrelizumab, an investigational therapy for rheumatoid arthritis by Roche Holding AG and Biogen Idec have been suspended after it caused deaths in some patients in trials.

Ocrelizumab is a humanized monoclonal antibody that selectively binds to a particular protein – the CD20 antigen – on the surface of B-cells, which are believed to play a critical role in immunologic diseases.

Ocrelizumab binds to and eliminates CD20-positive B-cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and eventually return to normal levels.

Ocrelizumab is also being studied in patients with multiple sclerosis.

In December 2009, Roche announced Phase III study (STAGE) of ocrelizumab given in combination with methotrexate (MTX) met its primary endpoint of improving signs and symptoms (as measured by American College of Rheumatology or ACR20 response) in rheumatoid arthritis (RA) patients who had an inadequate response to MTX at both 24 and 48 weeks.

The FILM study in MTX-naïve RA patients was placed on clinical hold following an assessment of benefit to risk in this specific  rheumatoid arthritis patient population.

The BELONG study in lupus nephritis patients was previously halted due to serious and opportunistic infection signals.

Roche and Biogen Idec announced their decision to suspend ocrelizumab treatment of patients in the rheumatoid arthritis (RA) programme following the recommendation of the independent ocrelizumab RA & Lupus Data and Safety Monitoring Board (DSMB) based on their assessment of the studies in rheumatoid arthritis (SCRIPT, FEATURE, FILM and STAGE) and lupus (BELONG and BEGIN).

The DSMB concluded that the safety risk outweighs the benefits observed in these specific patient populations at this time.

The DSMB review detected an infection related safety signal which included serious and opportunistic infections, some of which were fatal.

“Patient safety is of the utmost importance in all of our drug development programmes. In light of the DSMB recommendations we have decided to suspend Ocrelizumab treatment in the RA clinical development programme .” said Hal Barron, MD executive vice president and Chief Medical Officer at Roche.

The SCRIPT trial in patients who inadequately responded to one or more TNF antagonists and the FILM trial remain blinded. A detailed analysis of all of the data will be conducted to help further inform the future of the Ocrelizumab RA clinical programme.

Ocrelizumab is also being evaluated for relapsing remitting multiple sclerosis (RRMS). The treatment in the ocrelizumab RRMS Phase II study is on-going at this time.

Headquartered in Basel, Switzerland, Roche is the world’s largest biotech company with  medicines in oncology, virology, inflammation, metabolism and CNS.

Rheumatoid arthritis is a debilitating autoimmune disease that affects an estimated 1.3 million Americans and hinders daily activities.

The damage that occurs in RA is a result of the immune system attacking joint tissue, causing painful chronic inflammation, irreversible destruction of cartilage, tendons and bones, which often results in disability.

Common RA symptoms include inflammation of the joints, swelling, fatigue, stiffness and pain.  Additionally, since RA is a systemic disease, it can affect other tissues such as the lungs and eyes.

Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management.

In 2009, Roche had over 80’000 employees worldwide and invested almost 10 billion Swiss francs in R&D.

The Group posted sales of 49.1 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan.

Biogen Idec has products that address diseases such as lymphoma, multiple sclerosis, and rheumatoid arthritis.

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Synthemax surface, a new synthetic matrix for growing human embryonic stem cells (hESCs)in a scalable manner has been developed by under a collaboration and license agreement between Geron Corporation announced that Corning Incorporated.

Synthetic growth surfaces enable readily scalable and cost-effective production of undifferentiated hESCs and their differentiated therapeutic cells.

Biological surface coatings are expensive to produce, have lot-to-lot variability, and are subject to costly testing to ensure that they are pathogen-free.

Biological materials present a challenge for manufacturing human embryonic stem cells-derived products at scales required for therapeutic applications.

Geron and Corning have been working together to develop synthetic surface matrices to enhance the scalability of human embryonic stem cells-derived product manufacturing. The Corning Synthemax surface is the first such product to be commercialized.

Human embryonic stem cells express telomerase and have the capacity for indefinite replication in the undifferentiated state while retaining the potential to develop into all the cell types of the human body (pluripotency).

With these properties, human embryonic stem cells are the ideal starting material for large-scale production of cell therapies. To date, hESCs have been grown in complex culture systems that use biological materials, such as culture vessels with biological surface coatings.

“The synthetic growth matrix technology developed in our collaboration with Corning is an enabling platform to be used by Geron in producing new cell therapies for patients with degenerative diseases,” stated Jane S Lebkowski, Geron’s senior vice president and chief scientific officer, regenerative medicine.

This technology allows for more consistent, reliable and cost-effective manufacturing of human embryonic stem cells-derived products, he added.

The Synthemax surface supports the long-term propagation of hESCs cultured in a defined, xeno-free medium, while maintaining stable proliferation rates; characteristic phenotypic marker profile of the undifferentiated state; normal karyotype; and pluripotency.

Geron and Corning scientists presented data showing robust hESC growth and differentiation on the Synthemax surface at the September 2009 World Stem Cell Summit.

The laboratory products using the Synthemax surface and other synthetic surface matrices developed under the collaboration between Geron and Corning will be commercialized by Corning. Geron will receive a royalty on product sales and has exclusive rights to use the synthetic surface matrices, including the Synthemax surface, in the manufacturing of certain therapeutic products.

Currently, Corning’s 6-well plate with the Synthemax surface is available in North America.

Corning Incorporated is the world leader in specialty glass and ceramics.

Geron is developing biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes.

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TNFerade, an investigational drug to treat cancer which contains the gene for tumour necrosis factor alpha (TNFa), can suppress cancer metastases through activation of the immune system,

Preclinical study data indicate that local treatment of an animal tumour with TNFerade suppresses metastases to lymph nodes by activating CD8+ T cells.

Activation of these anti-tumour cells is mediated by Interferon-ß, a known potent immune regulator.

This preclinical study, “Ad.Egr-TNF and Local Ionizing Radiation Suppress Metastases by Interferon-ß-Dependent Activation of Antigen-specific CD8+ T Cells,” authored by investigators from the University of Chicago and Harvard Medical School, appears in the recent issue of Molecular Therapy.

“Although enhanced local control of cancer can contribute to improvements in patient survival, any suppression of metastases is an important aspect of cancer treatment,” noted Mark Thornton, GenVec’s senior vice president of Product Development in a press release.

TNFerade is an adenovector, or DNA carrier, which contains the gene for tumour necrosis factoralpha (TNFa), an immune system protein with potent and well-documented anti-cancer effects, for direct injection into tumours.

TNFerade, which is currently being investigated for pancreatic cancer, has been awarded Orphan Drug status providing potential financial and regulatory incentives by the U.S. Food and Drug Administration, its maker GenVec announced in November.

A Phase III trial comparing TNFerade along with standard of care therapy (defined as infusion 5-FU and radiation therapy, followed by gemcitabine or gemcitabine/erlotinib maintenance therapy) versus standard of care therapy in the treatment of locally advanced, unresectable pancreatic cancer is currently underway.

Patients will be randomly selected (2:1) to one of the two treatment groups.

Named PACT Study, phase II/III research study tested the safety and effectiveness of an investigational drug called TNFerade in combination with the standard of care therapy against locally advanced pancreatic cancer.

Pancreatic Cancer Clinical Trial with TNFerade (PACT) included approximately 330 patients who have pancreatic cancer that cannot be removed with surgery. Each patient received 5 weeks of treatment and 12 months of follow-up, followed by annual contacts.

Overall survival data in locally advanced pancreatic cancer patients treated with TNFerade in GenVec’s ongoing Phase III  were presented at the 45th American Society of Clinical Oncology Annual Meeting in Orlando, FL, in June.

TNFerade has also been and is currently being evaluated for its potential use in the treatment of several other cancers, including esophageal cancer, rectal cancer, and head and neck cancer.

TNFerade has been granted Fast Track product designation by the US Food and Drug Administration or its proposed use in the treatment of locally advanced pancreatic cancer.

The FDA grants orphan drug designation to drugs that may provide a significant therapeutic advantage over existing treatments and target conditions affecting 200,000 or fewer U.S. patients per year.

Orphan drug designation provides potential financial and regulatory incentives including study design assistance, waiver of FDA user fees, tax credits, and up to seven years of market exclusivity upon marketing approval.

“Orphan drug designation is a critical step for the development of TNFerade and will strengthen the TNFerade program at GenVec by offering potential clinical development and commercialization benefits,” stated Dr Paul Fischer,GenVec’s President and CEO.

TNFerade has also been and is currently being evaluated for its potential use in the treatment of several other cancers, including esophageal cancer, rectal cancer, and head and neck cancer.

GenVec is a biopharmaceutical company developing novel therapeutic drugs and vaccines.

GenVec uses its proprietary adenovector technology to develop vaccines for infectious diseases including influenza, HIV, malaria, foot-and-mouth disease, respiratory syncytial virus (RSV), and HSV-2. GenVec also discovers and develops novel treatments for hearing loss and balance disorders through a worldwide collaboration with Novartis.

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