More about PTC124

[Guest guest]

PTC Therapeutics Announces Interim Phase 2 Results of PTC124 in

Cystic Fibrosis

SOUTH PLAINFIELD, NJ UNITED STATES 03/31/2006

SOUTH PLAINFIELD, N.J., April 4 /PRNewswire/ -- PTC Therapeutics, Inc.

(PTC), a biopharmaceutical company focused on the discovery,

development, and commercialization of orally administered,

proprietary small-molecule drugs that target post-transcriptional

control processes, today announced interim results from Phase 2

clinical trials of PTC124 in patients with cystic fibrosis (CF) due

to a nonsense mutation. These interim data suggest that PTC124 may

have pharmacological activity that addresses the underlying cause

of CF in these patients.

PTC124 is an orally delivered investigational product candidate that

PTC is developing for the treatment of genetic disorders due to

nonsense mutations. Nonsense mutations are alterations in the

genetic code that prematurely halt the translation process, producing

a shortened, non-functional protein. Phase 2 clinical trials are

ongoing in the two initial indications being pursued, CF and Duchenne

muscular dystrophy (DMD) caused by nonsense mutations.

PTC is conducting two comparable Phase 2 clinical trials of PTC124 in

CF, one at the Hadassah University Hospital in Jerusalem, Israel, and

the other at four sites in the US (University of Alabama at

Birmingham Hospital and Clinics, AL; s Hopkins Hospital,

Baltimore, MD; Rainbow Babies' and Children's Hospital, Cleveland,

OH; and Denver Children's Hospital, Denver, CO). In each study,

patients receive two sequential two-week courses of treatment, first

at a lower and then at a higher PTC124 dose level.

The primary endpoint of these trials is the change in the CFTR

chloride channel activity (also known as chloride conductance).

Chloride conductance is evaluated using a standardized nasal

transepithelial potential difference (TEPD) procedure. Cystic

fibrosis patients lack sufficient CFTR protein and therefore have an

abnormal TEPD chloride conductance.

Fifteen patients have completed two cycles of treatment and data from

these patients were available for inclusion in the interim analysis.

Of these patients, three were from the U.S. trial and 12 were from

the Israeli trial. All patients had a nonsense mutation and multiple

signs and symptoms of CF, with most patients having lung dysfunction,

chronic bacterial infection of the lungs, pancreatic insufficiency,

and low body weights.

In these 15 patients, at both dose levels, statistically significant

results were observed in all three ways in which the TEPD endpoint was

assessed, including mean improvement in chloride conductance,

percentage of patients with a chloride conductance response, and

percentage of patients with a chloride conductance improvement into

the normal range. Statistically significant improvements in other

endpoints, including lung function and weight were also observed.

Several patients also reported improvement in well-being, decrease in

cough, decreased mucus thickness, and easier clearing of mucus.

" We believe that these results suggest that PTC124 has meaningful

pharmacological activity that is consistent with our hypothesis that

treatment with PTC124 can restore the production and function of CFTR

protein in patients with cystic fibrosis caused by a nonsense

mutation, " said Stuart W. Peltz, Ph.D., President and Chief Executive

Officer of PTC. " We also believe that this is the first time such

activity has been observed in a clinical trial of an oral therapy for

cystic fibrosis. "

PTC124 was generally well tolerated among the 15 patients included in

the interim analysis. All adverse events that were potentially drug-

related were mild in severity; there were no safety concerns

identified in patients' physical examinations, vital sign

measurements, or electrocardiograms; and no meaningful changes in

laboratory safety parameters were observed. There were

no dosing interruptions or trial discontinuations due to toxicity.

Evaluation of treatment compliance indicated that patients took more

than 98% of the intended total drug treatment at both the lower and

higher dose levels. Pharmacokinetic data indicated that PTC124 was

readily absorbed and desired plasma concentrations were achieved and

maintained at the first and fourteenth days of both the lower-dose

and higher-dose treatment courses.

PTC's Phase 2 CF and DMD clinical trials are ongoing. The interim

results do not necessarily predict favorable final results from these

ongoing CF or DMD trials or any future trial.

About PTC Therapeutics, Inc.

PTC is a biopharmaceutical company focused on the discovery,

development, and commercialization of orally administered,

proprietary small-molecule drugs that target post-transcriptional

control processes. Post-transcriptional control processes regulate

the rate and timing of protein production and are of central

importance to proper cellular function. PTC has assembled

proprietary technologies and extensive knowledge of post-

transcriptional control processes that it applies in its drug

discovery and development activities. PTC's current pipeline of

clinical and preclinical product candidates addresses multiple

indications, including genetic disorders, oncology, and infectious

diseases.

About PTC124

PTC124 is an orally delivered investigational product candidate in

development for the treatment of genetic disorders due to nonsense

mutations. Nonsense mutations are single-point alterations in the

genetic code that prematurely halt the translation process, producing

a shortened, non-functional protein. PTC124 has demonstrated

activity in preclinical genetic disease models harboring nonsense

mutations allowing the restoration of the production of full-length,

functional proteins. In Phase 1 clinical trials, PTC124 was

generally well tolerated, achieved target plasma concentrations

that have been associated with activity in preclinical models, and

did not induce ribosomal readthrough of normal stop codons.

Pharmacokinetic modeling of the Phase 1 results allowed development

of a dosing regimen for the Phase 2 studies in cystic fibrosis (CF)

and Duchenne muscular dystrophy (DMD).

It is estimated that 10% of the cases of CF and 13% of the cases of

DMD are due to nonsense mutations. PTC believes that PTC124 is

potentially applicable to a broad range of other genetic disorders in

which a nonsense mutation is the cause of the disease. The FDA has

granted PTC124 Fast-Track designations and Orphan Drug designations

for the treatment of CF and DMD due to nonsense mutations. PTC124

has also been granted orphan drug status for the treatment of DMD and

CF by the Committee for Orphan Medicinal Products (COMP) of the

European Medicines Agency (EMEA). PTC124's development is

supported by grants from the Muscular Dystrophy Association (MDA),

Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT), FDA's Office of

Orphan Products Development (OOPD), and by General Clinical Research

Center grants from the National Center for Research Resources (NCRR).

About Cystic Fibrosis (CF)

CF is among the most common life-threatening genetic disorders

worldwide. According to the Cystic Fibrosis Foundation, CF affects

approximately 30,000 adults and children in the United States and,

according to the European Cystic Fibrosis Foundation, it affects a

similar number of patients in Europe. CF occurs in approximately one

of every 3,500 live births, with approximately 1,000 new cases

diagnosed each year in the United States. There is a commercially

available genetic test to determine if a patient's CF is caused

by a nonsense mutation and it is estimated that nonsense mutations

are the cause of CF in approximately 10% of patients in the United

States. There is currently no available therapy to correct defective

CFTR production and function. Instead, available treatments for CF

are designed to alleviate the symptoms of the disease. These

treatments include chest physical therapy to clear the thick mucus

from the lungs, antibiotics to treat lung infections, and a mucus-

thinning drug designed to reduce the number of lung infections and

improve lung function. In addition, the majority of cystic fibrosis

patients take pancreatic enzyme supplements to assist with food

absorption in digestion. There is a significant unmet medical need

for a treatment for the underlying cause of CF. More information

regarding CF is available through the Cystic Fibrosis Foundation

(http://www.cff.org).

SOURCE PTC Therapeutics, Inc.

[Guest guest]

I think I remember chloride channels coming up in the presentations at

the conference; is there a possibility that this new drug could have

an effect on PSCers? Is this " nonsense " CF mutation the one that has

been associated with PSC? tx,

nina

> The primary endpoint of these trials is the change in the CFTR

> chloride channel activity (also known as chloride conductance).

> Chloride conductance is evaluated using a standardized nasal

> transepithelial potential difference (TEPD) procedure. Cystic

> fibrosis patients lack sufficient CFTR protein and therefore have an

> abnormal TEPD chloride conductance.

[Guest guest]

Dave ,Thanks for posting these.It sounds very encouraging.LeePTC Therapeutics Announces Interim Phase 2 Results of PTC124 in Cystic Fibrosis SOUTH PLAINFIELD, NJ UNITED STATES 03/31/2006

[Guest guest]

Hi Nina;

It has been suggested that certain mutations in the CFTR gene are

associated with PSC, but I don't know off-hand whether these are of

the " nonsense " type.

Look under CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR on

the " Online Mendelian Inheritance in Man " (OMIM) database:

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602421

and it has this to say about PSC:

" Primary sclerosing cholangitis (PSC), a slowly progressive cholestatic

liver disease characterized by fibroobliterative inflammation of the

biliary tract, leads to cirrhosis and portal hypertension and is a

major indication for liver transplantation. Sheth et al. (2003) stated

that 75 to 80% of cases were associated with inflammatory bowel disease

(IBD; 266600) and that 2.5 to 7.5% of patients with IBD develop PSC

(Lee and Kaplan, 1995). Sheth et al. (2003) hypothesized that

dysfunction of CFTR may explain why a subset of patients with IBD

develop PSC. They prospectively evaluated CFTR genotype and phenotype

in 19 patients with PSC compared with 18 patients with IBD and no liver

disease, 17 with primary biliary cirrhosis (PBC; 109720), 81 with CF,

and 51 healthy controls. They found an increased prevalence of CFTR

abnormalities in heterozygous state in PSC as demonstrated by molecular

and functional analyses, and concluded that these abnormalities may

contribute to the development of PSC in a subset of patients with IBD.

Eighty-nine percent of PSC patients carried genotypes containing the

1540G variant (602421.0023) resulting in decreased functional CFTR

compared with 57% of disease controls (P = 0.03). Only 1 of 19 PSC

patients had neither a CFTR mutation nor the 1540G variant. CFTR

chloride channel function assessed by nasal potential difference

testing demonstrated a reduced median isoproterenol response in PSC

patients compared with disease controls and healthy controls. "

I would suspect that if susceptibility to PSC is associated with only

one copy of the mutant gene (heterozygous state), then this medication

(PTC124) would not be of much help. I think this medication would only

help when a patient is homozygous for a nonsense mutation, allowing for

some restoration of gene function above zero.

In the heterozygous state you would already be at 50% gene function. In

the homozygous recessive state you would theoretically have 0% gene

function, and PTC124 might allow some restoration to say 5 - 10% gene

function?

But it is interesting nonetheless, as it would seem to be applicable to

literally hundreds of diseases that may have a genetic basis due to

nonsense mutations.

Remember also that cystic fibrosis was the first to give us high-dose

ursodiol (15 years ago!):

Colombo C, Crosignani A, Assaisso M, Battezzati PM, Podda M, Giunta A,

Zimmer-Nechemias L, Setchell KD 1992 Ursodeoxycholic acid therapy in

cystic fibrosis-associated liver disease: a dose-response study.

Hepatology 16: 924-930.

and more recently DHA:

Van Biervliet S, Van Biervliet JP, Robberecht E, Christophe A 2005

Docosahexaenoic acid trials in cystic fibrosis: a review of the

rationale behind the clinical trials. J. Cyst. Fibros. 4: 27-34.

So I think it is good to keep an eye on the development of new cystic

fibrosis medications.

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)

>

> I think I remember chloride channels coming up in the presentations

at

> the conference; is there a possibility that this new drug could have

> an effect on PSCers? Is this " nonsense " CF mutation the one that has

> been associated with PSC? tx,

> nina