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FDA was delayed by 12 months Zelmac was not granted FDA approval from in 2001…. Let me share the story…

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FDA was delayed by 12 months

Zelmac was not granted FDA approval from in 2001….

Let me share the story…

•The reason for the Agency’s request is a numerical imbalance between the treated and placebo groups with regard to abdominal surgeries and Gall Bladder Surgery

Delay in FDA : Granted July 02

Zelmac Group Placebo p Value n=2 965 n=1740 Abdominal surgeries 0.3% 0.17% 0.37Gall –Bladder surgery 0.16% 0.06% 0.22

FDA Granted July 2002

The FDA approval was granted with following post-approval commitments:

Perform a gallbladder mechanistic study in healthy volunteers.

Perform a placebo controlled study to evaluate the intermittent and long-term efficacy.

Perform a post marketing surveillance study to evaluate

the frequency of gallbladder surgeries and other

abdominal and pelvic surgeries.

Zelmac indication is in women only

What about male patients??? Is it safe ? Why does it not work in men?

Zelmac –in males

“tegaserod lacks efficacy is inaccurate” Zelmac has shown significant improvement in bowel

habit (number of bowel movements and stool consistency

No evidence on primary end point (SGA score) due to relative small numbers of male patients investigated

SGA of Relief in individual studies: placebo subtracted values at endpoint , by gender

Study

B 351Responder rate%

P-value

11.6 13.7

0.007 0.003

B 301

B 3072

FEMALE MALE

Adjusted1 Unadjusted

13.6 15.6

<0.001 <0.001Responder rate%

P-value

Responder rate%

P-value9.3 11.0

0.008 0.008

2.2 14.4

0.848 0.218

7.2 1.0

0.411 0.912

9.3 11.2

0.221 0.179

Adjusted Unadjusted

1.Adjusted for laxative intake, availability of SGA data, and treatment duration

2. 4mg/d instead of 12mg/d

Percent change from baseline in number of bowel movements in males

at endpoint

Study Placebo4mg/d 12mg/d

% Therap. Gain(%) p-value % therap gain % p-value

B301 33.3 47.1 13.8 0.002 64.8 31.5 0.001

B351 10.7 36.4 25.7 0.016 37.7 27.0 0.060

B307 34.6 56.2 21.6 0.053 43.6 9.0 0.027

Comparison (%) of patients with adverse events, by gender and treatment (phase III database)

Adverse event frequency of Adverse Events (percent)

Tegaserod Placebo

Males Females Males Female

N=260 N-2186 N=130 N=1459

Abdominal pain 16 16 12 12Diarrhea 15 10 4 4Nausea 9 8 5 7Flatulence 7 7 2 6Dyspepsia 4 5 6 4Headache 14 18 13 14Dizziness 4 5 5 3Back pain 5 5 1 4Upper respiratory 4 6 6 6 tract infection

Safety in Males

In phase III studies 10% of the patients were male. The data suggests that there are no adverse event (AE’s) suggesting difference in tolerability

How do we deal with the issue of Men?

The number of men enrolled in clinical trials is around 10% , the small number is due to the natural distribution in IBS Ratio of 3:1

Efficacy in men on endpoint (overall SGA relief) could not be achieved in the studies – however Zelmac had a positive effect on Bowel movements and bowel consistency

The safety and tolerability in males showed no difference with females-

Our current data and indication cannot support use in males-

Incidence of Ovarian Cysts

I read/heard somewhere that Zelmac causes Ovarian Cysts??

Incidence of ovarian cyst: in clinical studies

9 patients: 1 Placebo and 8 on tegaserod

Confirmed after analysis in only 5 patients

2 of which had the diagnosis of OC before entering the study

The other 3 had other diagnosis (pelvic adhesions, peritubal cysts etc…)

“How effective is Zelmac in patients with alternating symptoms?”

A-IBS forms a substantial number of patients that can be seen in the clinics

Zelmac works best for female patients whose main symptom is constipation- we cannot recommend the use of Zelmac in

alternating patients and we leave it to your medical judgment

in patients currently experiencing diarrhea as a key symptom – we do not advise use of Zelmac since it might

result in intensifying this symptom

“How should patients who experience diarrhea while taking Zelmac be managed?”

Doctor , I understand this might be experienced by a few patients

“Doctor, diarrhea can be a pharmacological response to therapy with Zelmac. Therefore, it is reasonable to expect that it could be a possible side effect.”

The majority of the patients taking Zelmac who reported diarrhea had a single episode.

In most cases, diarrhea occurred within the first week of treatment.

Typically, the diarrhea resolved with continued therapy.

Overall, the discontinuation rate from the studies due to diarrhea was low –1.6% - among the patients taking Zelmac.”

Versus other medications….

What advantages does Zelmac have over other treatments, such as Duspatalin?

Or: “Have you conducted any studies comparing the efficacy of Zelmac against other treatments?”

Response: no comparative studies

I believe this is a valid question with a new therapy such as Zelmac

Zelmac is a the first drug to be effective on all key symptoms of c-IBS and there has been no comparative data versus other medications .

The seriousness of IBS

“Is IBS really that important when compared with life-threatening diseases?”

Two Key points to discuss

QOL of life of patients with IBS- lower than that of patients suffering with Diabetes Mellitus

“So, doctor you can see that IBS has a significant impact on suffers’ lives. What do you think about it?”

Patients have a significant impact on their life- such as work, traveling, socializing, eating etc…

Tachyphylaxis

“Is Tachyphylaxis a problem with Zelmac?”

“Because response rates in clinical trials did not decrease between Month 1 and Month 3, and actually increased slightly, Tachyphylaxis does not appear to be an issue with the administration of Zelmac.”

Duration of Therapy and onset of effect

Zelmac has been studied for a duration of 12 weeks as agreed with FDA in terms of clinical study design

Onset of action was fast in most patients, during 1 week for symptoms of pain and bloating and 1 day for symptoms of constipation

It is recommended to evaluate response after a period of 4 weeks and to continue therapy to up to 12 weeks.

When can I re-challenge

No available data on intermittent therapy however some post marketing studies are ongoing

We have no data to support re-challenge however as with most chronic and acute syndromes clinical judgement is to be used