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DewDiligence

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Re: DB9 post# 3576

Thursday, 06/28/2007 3:19:02 AM

Thursday, June 28, 2007 3:19:02 AM

Post# of 19309
Here’s the MM-093 poster presentation from
EULAR corresponding to the abstract from
May in #msg-19852681. The discussion below
makes it clear why a higher dose of MM-093
(60mg) is currently being tested. (This info
is c/o our moderator, floblu; sorry, no link.)

>>
MM-093 Is Safe and Well Tolerated in an
Exploratory Phase-2 Study; Patients With
Highest Serum Levels of MM-093 Achieved
Robust Clinical Responses

A. Sawitzke, J. Murray

U of Utah School of Medicine, Division of Rheumatology, Salt Lake City, UT. Merrimack Pharmaceuticals, Inc., Cambridge, MA.

Introduction

MM-093 is a non-glycosylated version of Human alpha-fetoprotein (hAFP) produced by recombinant DNA technology in a transgenic goat system. hAFP is an endogenous protein that is present in the serum of healthy adults at levels of 5-10ng/ml.

During pregnancy, hAFP is made by the fetal liver and represents the major serum protein in the fetus, reaching levels of 3000–5000mcg/ml during the second trimester and falling to 50mcg/ml at term. The hAFP produced by the fetus enters the amniotic fluid at levels of 500mcg/ml and the maternal serum at levels of 0.3–0.5mcg/ml during the third trimester of pregnancy. Serum hAFP levels in both infants and mothers return to normal levels of 0.005–0.010mcg/ml within a few weeks of delivery. In addition, several patients have been described in the literature with a syndrome of hereditary persistent alphafetoprotein (HPAFP) that results in serum levels ranging from 20-200mcg/ml. Importantly, there have been no apparent adverse clinical symptoms associated with their high hAFP levels.

Levels of hAFP observed in the maternal serum during normal pregnancy appear to coincide with remission of several autoimmune disorders, including rheumatoid arthritis, multiple sclerosis, psoriasis and uveitis. The maternal levels of hAFP do not appear to be associated with significant immunosuppression, as demonstrated by the ability of both the pregnant female and the fetus to mount a normal immune response to infectious agents and vaccines during the third trimester. These data suggest that MM-093 may be a safe therapy for patients with autoimmune disorders.

Methods

Subjects aged 18-80 years with active RA were enrolled in the study provided they met the following key inclusion criteria: had ≥6 swollen joints and ≥6 tender joints and were on stable doses of MTX at 10–25mg/week. Subjects were randomly assigned in a 1:1:1:1 ratio to receive 2.5mg, 7.5mg or 20mg of MM-093 or placebo once a week for 24 weeks. Study drug was administered by the patient as a subcutaneous injection in the abdominal area. The primary efficacy endpoint was ACR20 response rate, and secondary efficacy endpoints included DAS28-CRP scores and EULAR responses.

Serum trough levels of MM-093 were measured at baseline, +12 weeks first dose and +24 weeks first dose. All statistical analyses were carried out on the intent-to-treat (ITT) population in patients that received at least one dose of MM-093 or placebo.

Results

Patient Demographics and Disease Characteristics

A total of 259 patients were randomized into the study and 189 patients completed the study. Patient demographics and disease characteristics at baseline were similar between groups (Table 1). Patients had a high level of disease activity at baseline, with all groups having mean DAS28-CRP scores above 5.5. However, mean CRP levels were lower than expected based on this high level of disease activity.

Safety

MM-093 was safe and well tolerated across all dosing groups. The number of patients experiencing an adverse event (AE); the relationship of AEs to study drug; and the severity of AEs was similar between groups. There were no dose relationships in any of the lab analyses or in any of the clinically significant lab abnormalities. There were a total of 19 serious adverse events (SAEs), but none of the SAEs that occurred in the active groups were thought to be related to study drug. The 20mg group [i.e. the highest dose tested] had the lowest incidence of SAEs. None of the patients had detectable levels of anti-MM-093 antibodies at study end.

There was one death in the study due to a suspected pulmonary embolism. The subject was a 78 year old and the death occurred 27 days after final dose during the follow up period. The subject was in the 2.5mg group and the event was unrelated to study drug in the opinion of the investigator.

Withdrawals

The overall withdrawal rate for this study was 27% (Table 2). The 20mg group had the highest incidence, with 22 withdrawals (33%). The most common reason for withdrawal, both across the entire population and within the 20mg group, was due to a worsening of RA symptoms that required initiation of a prohibited medication.

Efficacy

In the ITT, there did not appear to be a dose response in any of the analyzed efficacy endpoints. However, at the highest dose (20mg), there were both trends and statistically significant improvements in multiple efficacy endpoints when compared against placebo.

Of the ACR core components, MM-093 had the greatest effect on the change from baseline in swollen and tender joints (Table 3). These data suggest that MM-093 is biologically active at 20mg, but higher doses need to be tested to optimize the clinical response.

Pharmacokinetics

Prior to the study, pharmacokinetic (PK) modeling was completed using PK data from a Phase 1 study in healthy volunteers that evaluated single doses of 1-84mg of MM-093 and multiple doses of 5mg and 21mg every 4 days for 28 days and a Phase 1b study in RA that evaluated 21mg/week of MM-093 for 3 months. The modeling suggested that weekly doses of 2.5mg and 7.5mg of MM-093 would bracket maternal serum levels of AFP that are typically seen in the third trimester of pregnancy (i.e. ~0.3–0.5mcg/ml) and 20mg would result in approximately 3X the maternal levels of AFP in the third trimester (i.e. ~1.6mcg/ml). As predicted, the serum levels of MM-093 in the 2.5mg and 7.5mg groups in this study correlated to the maternal serum levels of AFP that are typically seen in the third trimester of pregnancy (Figure 1). However, the mean serum level of MM-093 in the 20mg group was slightly less than dose proportional and fell short of the predicted value of ~1.6mcg/ml. Furthermore, the variability was higher than expected across all groups, with coefficients of variation ranging from 53.1% to 105%. As a result, only 9 patients achieved serum levels of MM-093 above 1.6mcg/ml.

In the 9 patients that achieved MM-093 serum levels above 1.6mcg/ml, there was a more robust clinical response than across the entire 20mg group. 7/9 patients achieved the primary endpoint of ACR20 and 8/9 patients achieved a EULAR “good” or “moderate” response. The clinical response was even more dramatic as higher PK levels were achieved (i.e. above 2.0mcg/ml), with all 5 patients achieving an ACR20 response (Table 4). This data suggests that higher doses of MM-093 need to be administered to ensure that adequate serum levels are achieved.

An additional safety analysis was performed comparing the 9 patients with MM-093 serum levels above 1.6mcg/ml against the placebo group. Adverse event and serious adverse event rates were assessed. The most frequently occurring adverse event in patients above 1.6mcg/ml was injection site reaction, with 3/9 patients experiencing this event. However, all of the injection site reactions were classified as mild and resolved without action. There were no SAEs in any of the 9 patients. Although the data set is limited to 9 patients, this data is consistent with the safety profile of MM-093 that was seen across all dosing groups in this study and suggests that higher doses of MM-093 can be administered without compromising safety.

Conclusions

• MM-093 was safe and well tolerated at all doses in an exploratory Phase 2 dose-ranging study. In addition, none of the patients had detectable levels of anti-MM-093 antibodies at study end. As a result, MM-093 has the potential to be a safe alternative in the treatment of rheumatoid arthritis.

• Due to the increased withdrawal rate and the variability in serum levels of MM-093 in the highest dosing group, there were fewer than expected patients that achieved the expected serum levels of 1.6mcg/ml of MM-093 at study end.

• In the 9 patients that achieved serum MM-093 levels above 1.6mcg/ml in this study, the clinical response was more robust than seen across the entire 20mg group, with 7/9 patients (78%) achieving the primary endpoint of ACR20.

• Based on the PK variability seen in this study, higher doses of MM-093 may need to be administered to ensure that patients achieve levels of MM-093 above 1.6mcg/ml.

• A Phase 2 study is currently underway evaluating 60mg/week of MM-093 versus placebo in patients with active RA despite MTX treatment [#msg-18721015]. At this dose, it is expected that most patients will achieve serum levels of MM-093 above 1.6mcg/ml, which is approximately 3X the maternal levels of AFP in the third trimester.
<<

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