Chest
Volume 125, Issue 1, January 2004, Pages 143-149
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Clinical Investigations
CYSTIC LUNG DISEASE
A Phase I Trial of Intranasal Moli1901 for Cystic Fibrosis

https://doi.org/10.1378/chest.125.1.143Get rights and content

Background

The peptide drug Moli1901 activates an alternative chloride channel that is present in cystic fibrosis (CF) nasal and airway epithelia. Doing so bypasses the dysfunctional CF transmembrane regulator.

Study objective

To determine whether intranasal Moli1901 is safe, tolerable, and will induce chloride transport in healthy volunteers and CF subjects.

Design

A single-blind (to the participant), randomized, placebo-controlled, dose-escalation study of intranasal Moli1901 was performed in four healthy non-CF participants and four participants with CF. Drug or placebo was administered by intranasal superfusion, and nasal potential difference responses were continuously monitored during sequential dose escalations at 1-min intervals from 0.01 through 10 μmol/L.

Results

Neither Moli1901 nor placebo were associated with visible changes such as edema, erythema, drainage, secretions, or ulcer formation. No elevations in lactate dehydrogenase, albumin, or cell counts were observed in nasal lavage fluid after administration. No clinically significant changes in FEV1 or other toxicity parameters occurred. Changes in the nasal potential difference (NPD) induced by chloride-free, amiloride-containing Ringers solution and by subsequent superfusion with the same solution plus 10 μmol/L isoproterenol were consistent with both an acute and a sustained change in chloride transport in response to Moli1901. A similar analysis of NPD in the four CF participants demonstrated an acute response that resolved more quickly. A dose-response relationship to Moli1901 was observed in non-CF participants, but a greater range of variability within the CF participants contributed to the lack of a clear dose-response relationship in this group.

Conclusion

Moli1901 stimulates chloride transport in normal and CF nasal epithelia in vivo, but may have a shorter duration of action in CF participants.

Section snippets

Study Design

This was a phase I trial that was randomized, placebo controlled, and single blind to the participant. The study protocol was approved by the Johns Hopkins University School of Medicine Joint Committee on Clinical Investigation (institutional review board) and the Johns Hopkins General Clinical Research Center, and was performed in the Johns Hopkins Hospital Outpatient General Clinical Research Center. Participants gave informed consent.

Participant Characteristics

Healthy, non-CF participants 18 to 40 years of age were

Subjects

Four non-CF (one woman and three men) and four CF participants (three women and one man) enrolled and completed the study. One CF subject presented at screening with an elevated serum glucose level that was subsequently evaluated and treated.

Safety

No adverse events related to Moli1901 occurred during this study. There was no change in FEV1 after exposure to Moli1901 in either group. All eight subjects had no statistically significant change in any safety parameter after exposure to Moli1901.

All

NPD in Non-CF and CF Participants

Baseline assessments and postdose assessments were obtained for all subjects for both control and drug-treated nostrils. Follow-up NPD measurements without Moli1901 were repeated weekly for at least a month and until the responses were within 20% of baseline to assess duration of drug effect.

The baseline NPD, amiloride-sensitive response, chloride-free response, and isoproterenol response for normal and CF participants prior to drug exposure (Table 1) were compared. These data show that the

Discussion

The respiratory epithelium lining the inferior turbinate resembles structurally and functionally the epithelium lining the upper airways and can be used as a surrogate region for evaluating compounds that modulate airway epithelial ion transport.9 NPD measurements of basal or resting potential difference reflect the dominant sodium flux from lumen to submucosal space.1011 The contribution of sodium absorption to this potential difference is estimated by superfusing with amiloride to inhibit

Conclusions

In conclusion, Moli1901 was safe and well tolerated in nasal epithelium exposed to a concentration of up to 10 μmol/L. Chloride secretion was induced at 1 μmol/L, 3 μmol/L, and 10 μM in normal volunteers. CF participants also generated chloride secretion in response to Moli1901 at 3 μM, but more variability was observed. Further, these studies justify the conduct of a pilot efficacy study of Moli1901 in CF.

ACKNOWLEDGMENT

The authors thank Ms. Lois Brass-Ernst and Ms. Terry Williams for the execution of this clinical trial.

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This work was supported in part by SBIR grant 1 R43HL57070-01A1, The North Carolina Biotechnology Center, NIH/NCRR grant RR-00052 at The Johns Hopkins University General Clinical Research Center, Molichem Medicines, Inc., and the Cystic Fibrosis Foundation.

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