WINRHO (Page 5 of 7)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Treatment of ITP

WinRho SDF has been shown to increase platelet counts in non-splenectomized, Rho (D)-positive patients with ITP. Platelet counts usually rise within one to two days and peak within seven to 14 days after initiation of therapy. The mechanism of action is not completely understood, but is thought to be due to the formation of anti-Rho (D)-coated RBC complexes, which are preferentially removed by the reticuloendothelial system, particularly the spleen. This results in Fc receptor blockade, thus sparing antibody-coated platelets.9,10

Suppression of Rh Isoimmunization

The mechanism by which Rho (D) immune globulin suppresses immunization to Rho (D)-positive RBCs is not completely understood.

WinRho SDF when administered within 72 hours of a full-term delivery of a Rho (D)-positive infant by a Rho (D) negative mother will reduce the incidence of Rh isoimmunization from 12-13% to 1-2%. The 1-2% is, for the most part, due to isoimmunization during the last trimester of pregnancy. When treatment is given both antenatally, at 28-weeks gestation, and postpartum, the Rh immunization rate drops to about 0.1%.13,14

When 600 IU (120 mcg) of WinRho SDF is administered to pregnant women, passive anti-Rho (D) antibodies are not detectable in the circulation for more than six weeks and therefore a dose of 1,500 IU (300 mcg) should be used for antenatal administration.

12.2 Pharmacodynamics

In a clinical study with Rho (D)-negative volunteers (nine males and one female), Rho (D)-positive RBCs were completely cleared from the circulation within 8hours of intravenous administration of WinRho. There was no indication of Rh isoimmunization of these subjects at six months after the clearance of the Rho (D)-positive RBCs.

12.3 Pharmacokinetics

IM versus IV Administration (Lyophilized Powder)

In a clinical study involving Rho (D)-negative volunteers, two subjects received 600 IU (120 mcg) WinRho by intravenous (IV) administration and two subjects received this dose by intramuscular (IM) administration. Peak levels (36 to 48 ng/mL) were reached within two hours of IV administration and peak levels (18 to 19 ng/mL) were reached at five to 10 days after IM administration. Although no statistical comparisons were made, the calculated areas under the curve were comparable for both routes of administration. The t½ for anti-Rho (D) was about 24 days following IV administration and about 30 days following IM administration.

Lyophilized Powder versus Liquid Formulation

In two comparative pharmacokinetics studies, 101 volunteers were administered the liquid or lyophilized formulation of WinRho SDF intravenously (n=41) or intramuscularly (n=60). The formulations were bioequivalent following IV administration based on area under the curve to 84 days and had comparable pharmacokinetics following IM administration. The average peak concentrations (Cmax ) of anti-Rho (D) for both formulations were comparable following IV or IM administration and occurred within 30 minutes or 2-4 days of administration, respectively. Both formulations also had similar elimination half-lives (t½ ) following IV or IM administration.

14 CLINICAL STUDIES

14.1 Treatment of ITP

Efficacy was documented in four subgroups of patients with ITP:

Childhood Chronic ITP

In an open-label, single arm, multicenter study, 24_non-splenectomized, Rho (D)-positive children with ITP of greater than six-months duration were treated initially with 250 IU/kg (50 mcg/kg) WinRho [125 IU/kg (25 mcg/kg) on days 1 and 2, with subsequent doses ranging from 125 to 275 IU/kg (25 to 55 mcg/kg)]. Response was defined as a platelet increase to at least 50,000/mm3 and a doubling of the baseline. Nineteen of 24 patients responded for an overall response rate of 79%, an overall mean peak platelet count of 229,400/mm3 (range 43,300 to 456,000), and a mean duration of response of 36.5 days (range 6 to 84).15

Childhood Acute ITP

A multicenter, randomized, controlled trial comparing WinRho to high dose and low dose Immune Globulin Intravenous (Human) (IGIV) and prednisone was conducted in 146 non-splenectomized, Rho (D)-positive children with acute ITP and platelet counts less than 20,000/mm3. Of 38 patients receiving WinRho [125 IU/kg (25 mcg/kg) on days 1 and 2], 32 patients (84%) responded (platelet count ≥ 50,000/mm3) with a mean peak platelet count of 319,500/mm3 (range 61,000 to 892,000), with no statistically significant differences compared to other treatment arms. The mean times to achieving ≥ 20,000/mm3 or ≥ 50,000/mm3 platelets for patients receiving WinRho were 1.9 and 2.8 days respectively. When comparing the different therapies for time to platelet count ≥ 20,000/mm3 or ≥ 50,000/mm3 , no statistically significant differences among treatment groups were detected, with a range of 1.3 to 1.9 days and 2.0 to 3.2 days, for IGIV and prednisone respectively.16,17

Adult Chronic ITP

Twenty-four non-splenectomized Rho (D)-positive adults with ITP of greater than six-months duration and platelet counts < 30,000/mm3 or requiring therapy were enrolled in a single-arm, open-label trial were treated with 100 to 375 IU/kg (20 to 75 mcg/kg) WinRho [mean dose 231 IU/kg (46.2 mcg/kg)]. Twenty-one of 24 patients responded (increase ≥ 20,000/mm3) during the first two courses of therapy for an overall response rate of 88% with a mean peak platelet count of 92,300/mm3 (range 8,000 to 229,000).18,19

ITP Secondary to HIV Infection

Eleven children and 52 adults, who were non-splenectomized and Rho (D)-positive, with all Walter Reed classes of HIV infection and ITP, with initial platelet counts of ≤ 30,000/mm3 or requiring therapy, were treated with 100 to 375 IU/kg (20 to 75 mcg/kg) WinRho in an open label trial. WinRho was administered for an average of 7.3 courses (range 1 to 57) over a mean period of 407 days (range 6 to 1,952). Fifty-seven of 63 patients responded (increase ≥ 20,000/mm3) during the first six courses of therapy for an overall response rate of 90%. The overall mean change in platelet count for six courses was 60,900/mm3 (range -2,000 to 565,000), and the mean peak platelet count was 81,700/mm3 (range 16,000 to 593,000).18-20

14.2 Suppression of Rh Isoimmunization

A study was conducted in 1,186 non-sensitized, Rho (D)-negative pregnant women in cases in which the blood types of the fathers were Rho (D)-positive or unknown. WinRho was administered according to one of three regimens: 1) 93 women received 600 IU (120 mcg) at 28 weeks; 2) 131 women received 1200 IU (240 mcg) each at 28 and 34 weeks; 3) 962 women received 1200 IU (240 mcg) at 28 weeks. All women received a postnatal administration of 600 IU (120 mcg) if the newborn was found to be Rho (D)-positive. Of 1,186 women who received antenatal WinRho, 806 were given WinRho postnatal following the delivery of a Rho (D)-positive infant, of which 325 women underwent testing at six months after delivery for evidence of Rh isoimmunization. Of these 325 women, 23 would have been expected to display signs of Rh isoimmunization, however, none was observed (p <0.001 in a Chi-square test of significance of difference between observed and expected isoimmunization in the absence of WinRho).

15 REFERENCES

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