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http://www.neutecpharma.com/mycograb.html

Mycograb®

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.

Breast Cancer

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.