NeuTec Pharma Ltd
NeuTec Pharma Ltd. was a Pharmaceuticals company located in Lloyd St N, Manchester, United Kingdom. This site was developed by Pharma around 2003 to promote their company and NeuTec's two leading products Mycograb® and Aurograb®. In July 2006 the company was acquired by Novartis Pharma AG. The site's domain eventually expired and the information regarding NeuTecPharma Ltd disappeared from the WWW.
I first heard about Mycograb® and Aurograb® when I was in London, UK attending a 2006 onference about the use of healthcare data analytics and how it can revolutionize the entire healthcare industry. I work for a progressive software development firm and we have observed 3 current trends for improving medical outcomes with the use of medical data analytics. The conference was a means for my company to network, perhaps find new clients, as well as contribute to the ongoing discussions regarding the coding involved to create the means to gather data and analyze it. The conference was informative. I took a side trip to see a potential client in Manchester where NeuTec Pharma Ltd. was located. It seemed that everyone I met was talking about Novartis Pharma AG acquiring NeuTec Pharma Ltd and what it might mean for the pharma industry. in all it was a successful trip with my acquiring a number of good leads. I continued to follow the two drugs, Mycograb® and Aurograb®. In 2008 Novartis decided to pull the plug on Aurograb. Pundits said that Novartis' high-premium $569m takeover of NeuTec Pharma in 2006 was perhaps now looking like an increasingly expensive mistake. Then in 2010 Novartis abandoned their continuing development of anti-fungal agent Mycograb, highlighting the high cost of R&D failure in the pharma industry.
Nevertheless when I recently discovered that the domain was available, I bought it with the intent of restoring some of its original content found in its archived pages. I believe that the information on neutecpharma.com's archived pages is still important and should be available for online viewing if for no other reason than for historical purposes.
PLEASE NOTE THAT THIS PAGE CONTAINS SELECTED ARCHIVED CONTENT FROM THE ORIGINAL SITE.
NeuTec Pharma plc is a biopharmaceutical company formed in 1997 which specialises in the development of genetically recombinant antibodies, or “grabs”, for the treatment of life-threatening infections. The development of NeuTec's products differs from the traditional approach used by conventional pharmaceutical companies which screen numerous chemical compounds for activity against bacteria and fungi. Many of these compounds will be too toxic for human use. In contrast, NeuTec identifies naturally occurring potentially protective antibodies from patients who have recovered from bacterial and fungal infections and then uses these to generate “grabs” to treat these infections. As a result, these “grabs” are likely to be intrinsically saferthan antibiotics.
NeuTec's Two Leading Products are Mycograb® and Aurograb ®
NeuTec's two leading products are Mycograb®, which targets systemic candidiasis, and Aurograb®, which targets Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (“MRSA”).
Over the last eight years NeuTec has made significant progress in developing its products and research programmes and has recorded a number of key achievements including:
- the large scale cGMP production of Mycograb® and Aurograb®
- the granting of Orphan Drug Status for Mycograb® in Europe by the EMEA
- the granting of Orphan Drug Status for Mycograb® by the US Food and Drugs Administration ("FDA") in 2002
- the submission of an Investigational New Drug ("IND") application with the US Food and Drugs Administration ("FDA") in February 2003
- completion of, and reporting upon the results from, the successful confirmatory study on Mycograb®in invasive candidiasis in July 2004
- initiation of a compassionate use programme for Mycograb® in January 2005
- validated application made to the EMEA for market authorisation in the treatment of invasive candidiasis in March 2005
- 1st patient entered in a multi-centre phase Ib study to evaluate Mycograb® administered in metastatic breast cancer patients in September 2005
- successful application to the FDA for an IND to carry out phase III trial using Mycograb® as adjunctive therapy for cryptococcal meningitis in patients with AIDS
- the completion of a Phase II clinical trial on Aurograb® in June 2003. The study demonstrated a profile that suggests likely activity against MRSA
- commencement of a pan European phase III clinical trial on Aurograb® in May 2004
- the development of the FABTEC© platform technology for the identification of new therapeutic antibody fragments
- 18 families of patents have been filed and over 70 patents have been granted worldwide protecting the intellectual property created by the company's research and development programmes
- the identification of further potential products from its research programme for future development
Research and Development
NeuTec identifies the key antigens and associated antibodies by characterising the antibody responses produced by patients who recover from an infection and then comparing them with those in patients who die from the infection. "Grabs" against these patented antigens are derived, using the Company's FabTec©platform technology, from patients who have recently recovered from the relevant infection and are therefore actively producing high levels of protective antibodies. As a result, these "grabs" are of high specificity, affinity and potency against the microbial target.
The manufacture of pharmaceutical products is subject to strict governmental and regulatory controls to enforce cGMP. Accordingly, to establish such a manufacturing facility requires substantial capital investment and management resources. At present, NeuTec outsources its manufacturing requirements in line with many other biopharmaceutical companies at a similar stage of development.
Commercial Product Development
NeuTec's commercial strategy involves a combination of own-product discovery and development together with subsequent collaborative partnering with pharmaceutical companies, to commercialise its products, at the appropriate time. The Company will evaluate the opportunity to form such strategic alliances with other pharmaceutical companies on a product-by-product and territory-by-territory basis. NeuTec proposes to make direct sales in Europe for Mycograb® using a small focused sales team once market authorisation has been achieved.
Mycograb®, is a “grab” targeting the immunodominant antigen heat shock protein 90 (“hsp90”) for the treatment of systemic candidiasis. This is a life-threatening fungal infection most commonly due to the yeast species Candida albicans and, less commonly, Candida krusei, Candida parapsilosis or Candida tropicalis.
Systemic fungal infections are estimated at 320,000 incidences per year worldwide. Most common is systemic candidiasis, representing approximately 70 per cent of all such infections with a mortality rate of up to 40 per cent. Mycograb® has completed a confirmatory study in the treatment of systemic candidiasis and has applied to the EMEA for market approval in Europe. The drug may also be active against other fungal infections and breast cancer.
At particular risk are low birth-weight babies, post surgical patients, patients whose immune systems have been compromised, such as by therapies for cancer, bone marrow transplant recipients and patients on peritoneal dialysis. For example, in a German study, over 12 per cent of patients receiving bone marrow transplants developed systemic candidiasis. Indeed general medical advances in these areas over recent decades have almost certainly contributed to an increase in the number of patients at risk.
The standard therapy for the treatment of systemic candidiasis is amphotericin B which is available off- licence. Whilst it is inexpensive and widely prescribed, its use is limited by toxicity and lack of efficacy. Severe reactions, especially kidney and liver toxicity, are common and so, to reduce the incidence of such side-effects, more expensive lipid-based formulations are widely used. These are less toxic but have not been associated with improved efficacy. Alternatively, drugs such as fluconazole can be given although certain species of Candida, such as Candida krusei, are intrinsically resistant and indeed fluconazole resistance has now emerged in Candida albicans itself. Accordingly, there is a need for a more effective and safe form of treatment for Candida with a broad spectrum of activity.
Since 1998, Mycograb® has developed from a crude preparation produced in two litre batches in the laboratory into a well defined product manufactured to GMP standards in a large scale fermenter. Over this period the company has itself built up substantial technical knowledge regarding the processes required to achieve successful large scale production and GMP compliance including the fermentation, downstream processing and freeze drying of the final purified product.
The final formulation and convenient method of storage, as a stable freeze dried powder in glass vials, was developed in-house and then optimised using the large scale facilities of a third party manufacturer.
Mycograb® has the following properties as an antifungal agent:
- intrinsic antifungal activity;
- synergistic activity with amphotericin B: the combined use of the two agents together giving greater activity than either agent alone; and
- a broad spectrum of activity against all Candida species examined including fluconazole-resistant Candida albicans and Candida krusei.
This activity has been demonstrated using laboratory assays analogous to those used to test traditional antifungal agents including minimum inhibitory levels and models of the infection. Given its synergy with amphotericin B, Mycograb® was evaluated in a confirmatory clinical trial in combination with liposomal preparations of amphotericin B (Abelcet and AmBisome) to determine whether this combination therapy is more effective than amphotericin B alone.
The hsp90 antigen targeted by Mycograb® is also present in the fungus Aspergillus which is the cause of invasive aspergillosis, a less common but even more lethal systemic fungal infection. Preliminary laboratory data suggests Mycograb® may also have activity against this fungus and future clinical trials may investigate the efficacy of Mycograb® against invasive aspergillosis.
Additionally, a successful application to the FDA for an Investigational New Drug (“IND”) has been achieved for a phase III study to assess the efficacy and safety of Mycograb® as adjunctive therapy for cryptococcal meningitis in patients with AIDS. The trial will take place in centres in the USA, South America and South Africa.
Orphan Drug Status has been granted in Europe by the EMEA and in the USA by the FDA for the use of Mycograb® against invasive fungal infections including systemic candidiasis and invasive aspergillosis.
Mycograb® positive clinical results:
In July 2004 the company announced the successful achievement of clinical end points from a multinational, double-blind, placebo-controlled trial involving 10 European countries and the USA. The trial was conducted in 139 patients with invasive candidiasis who received conventional treatment with lipid-based formulation of amphotericin B combined with a five day course of either Mycograb® or placebo.
- Primary end point - 84% overall response rate vs 48% in placebo control group: To be regarded as a success, patients had to show both a complete clinical response ("cure") and a mycological response (culture-confirmed clearance of the infection in the laboratory) at Day 10. The trial showed a highly statistically significant difference (P value < 0.001) in the overall response rates (clinical and mycological response) between the placebo control group and those receiving Mycograb®. The positive response rate of the group receiving mono-therapy was 48% compared to 84% in the group recieving Mycograb® with amphotericin B.
- Secondary end point - In addition, separate analysis of each of the two components (clinical response and mycological response) showed a highly statistically significant difference between the two groups (P value < 0.001).
- Secondary end point - less deaths due to candidal infection: In the group receiving mono-therapy, candida-attributable mortality was 18%, whereas in the group receiving additional therapy with Mycograb® this fell to 4%, a statistically signifiant difference (P value < 0.025).
- Secondary end point - faster eradication of fungus: A highly statistically significant difference between the two groups (P value <0.001) occurred in the rate of culture-confirmed clearance of the infection (Mycograb® 3 days, mono-therapy 23 days).
- In March 2005 a validated application was made to the EMEA for market authorisation in the treatment of invasive candidiasis.
In September 2005 the company commenced a clinical study in breast cancer patients. The phase Ib, pharmacokinetic, multi-centre, open label study evaluated the safety and efficacy of Mycograb® administered in combination with Docetaxel in metastatic or recurrent breast cancer patients.
According to the American Cancer Society, breast cancer is the most common cancer among women, except for non-melanoma skin cancers and it is estimated that in 2005 about 211,240 new cases of invasive breast cancer will be diagnosed among women in the United States. Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer. The chance that breast cancer will be responsible for a women’s death is about 1 in 33 (3%). In 2005, about 40,110 women and 470 men will die from breast cancer in the United States. Currently there is no curative therapy for metastatic breast cancer despite early diagnosis, and the five year survival rate for advanced cancers is only 18%.
Mycograb® is a human genetically recombinant antibody (‘grab’) that binds to heat shock protein 90 (‘hsp90’) which has been identified as a tumour marker which appears on the outside of certain cancer cells (as with fungi) and is needed for cancer cell survival. The growth of cancer cells is particularly sensitive to the effects of hsp90’s inhibition and this anti-cancer activity has been seen in a series of vitro studies looking at the killing of human cancer cell lines.
There have been over 460 papers describing the involvement of hsp90 in the development of cancer. Consequently, hsp90 proteins are widely being evaluated as targets for cancer chemotherapy in combination with other drugs and as stand alone therapy. There are 21 on-going trials, involving a variety of cancers, using agents based on variants of the chemical hsp90 inhibitor geldanamycin. Dose-limiting toxicity, however, is a major hurdle in the development of chemical hsp90 inhibitors. Mycograb® differs from all other hsp90 inhibitors in having been originally developed for the treatment of fungal infections.
Aurograb® is a "grab" targeting Staphylococcus aureus including MRSA and the recently emerged VISA. Staphylococcus aureus is the bacterium responsible for the largest proportion of hospital-acquired bacterial infections. MRSA is now endemic in hospitals around the world with an estimated 1.5 million cases per year worldwide. MRSA causes significant morbidity with mortality from MRSA bloodstream infections of up to 50 per cent.
Vancomycin is an antibiotic of last resort being a cause of nephrotoxicity, ototoxicity and bone marrow toxicity. Moreover, intermediate sensitivity to vancomycin has recently surfaced among MRSA strains in Japan, the USA and Europe. The emergence of VISA has been described by The Lancet as an “apocalypse now” scenario and highlights the need for new and more effective therapies.
cGMP manufacture of Aurograb® was completed in June 2001 involving fermentation, downstream processing and freeze drying batches of the final purified product. Pre-clinical studies were successfully completed in November 2001 and a CTX was successfully applied for from the MCA in January 2002. Clinical trials commenced in mid 2002.
Aurograb® has the following properties as an antistaphylococcal agent:
- intrinsic activity against staphylococci;
- synergistic activity with vancomycin: the combined use of the two agents together giving greater activity than either agent alone; and
- a broad spectrum of activity against different strains of Staphylococcus aureus including the currently circulating epidemic strains of MRSA and VISA.
This activity has been demonstrated using laboratory assays analogous to those used to test antistaphylococcal antibiotics, including minimum inhibitory levels and models of the infection. Given its synergy with vancomycin, the company anticipates that Aurograb® will be of particular benefit when prescribed in combination with vancomycin in the treatment of MRSA infections, both increasing efficacy and inhibiting the emergence of VISA.
In June 2006 the company completed a double-blind placebo-controlled phase III clinical trial. The study carried out in a total of 35 centres in 6 European countries and involved the recruitment of 161 adult hospitalized patients with deep-seated staphylococcal infections. The trial compared the effects of Aurograb® in combination with vancomycin versus vancomycin alone in the treatment of MRSA infections.
This trial follows the earlier phase IIb study which was completed in June 2003 and found the drug to be well tolerated and demonstrated a profile that supports likely activity against MRSA in man. Aurograb® has activity on its own against strains of MRSA, but when combined with vancomycin, the current “gold standard” treatment, is more effective than either drug used on its own. The activity is also evident in strains with partial resistance to vancomycin or linezolid. Fully resistant strains to vancomycin have also been reported.
Platform Technology: FABTEC©
Fabtec® is NeuTec Pharma’s platform technology for the identification of new therapeutic antibody fragments.
Fabtec® consists of four distinct steps
Identification and recruitment of appropriate individuals to provide blood specimens
Identification of the correct individuals to be included in the study is all important for extracting the best possible data. Information such as age, infection status and general health all influence the success of procedures further down the line.
Amplification, cloning and sequencing of antibody fragments
Much effort has been put into these steps to ensure that the data we produce matches the range of antibodies expressed in infection. The individual molecular biology techniques used at each stage of the antibody fragment library production have all been optimised in-house. NeuTec’s sequencing facilities allow for the production of up to 500,000 base pairs of data each week, with the option of doubling this capacity.
Analysis of sequence data and identification of potential therapeutic antibodies
The production of so much data would be pointless without the ability to interpret it. With the lack of any useful software on the market NeuTec bespoke developed software designed to handle the large amounts of antibody fragment data. The Fabtec® Warehouse now represents one of our most important tools in the identification of therapeutic antibodies.
Laboratory scale production of antibody fragments and investigation of their properties
Expression vectors have been specially designed by our molecular biologists for the expression of antibody fragments. These in-house vectors have been shown to express antibody fragments at high levels. A comprehensive series of tests are performed on the expressed antibody fragments to identify the activity of the antibody fragments and access their suitability for manufacture.
NeuTec Pharma has found that this process, for taking a disease from preliminary clinical investigation through to the creation of molecules ready for manufacturing for use in pre-clinical studies, has taken 3-6 months.
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Identification of an immunodominant drug efflux pump in Burkholderia cepacia.
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Recombinant antibodies: a natural partner in combinatorial antifungal therapy.
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Genetically recombinant antibodies: new therapeutics against candidiasis.
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Evaluation of Mycograb®, Caspofungin and fluconazole in combination against Cryptococcus neoformans by checkerboard and time-kill methodologies.
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Identification of ABC transporters in Vancomycin-resistant Enterococcus faecium as potential targets for antibody therapy.
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