(180) A first in human study to evaluate the safety, tolerability, and pharmacokinetics of GDC-6988 (ETD002), a selective inhaled potentiator of the TMEM16A chloride channel

Thursday, November 3, 2022

12:00 PM – 12:40 PM ET

Presenting Author(s)

Joshua M. Galanter, MD, MAS (he/him/his)

Lead Medical Director
Genentech
South San Francisco, California, United States

Co-Author(s)

Paul Russell

Head of Development
Enterprise Therapeutics
Falmer, United Kingdom
NL

Nicholas Lewin-Koh

United States
RZ

Rui Zhu

United States
KW

Kathy Woodward

United Kingdom
DM

David Morris

United States
DW

Denisa Wilkes

United Kingdom
DR

Daniel Repplinger

United States
PM

Paul Miller

United States
RW

Rachael White

United Kingdom
HC

Hubert Chen

United States

Background:

Background: Therapies that restore fluid transport at the airway surface are predicted to improve mucus clearance and reduce the frequency of pulmonary exacerbations. Although effective, CFTR modulator therapies are not currently indicated for ~10% of people with CF and do not fully relieve the disease, even in those for whom they are indicated. As such, there is an important need for novel approaches to address patients unsuitable for current CFTR modulator therapies and those who do not respond optimally. GDC-6988 is a potent and selective potentiator of TMEM16A, and is expected to enhance the opening of the chloride channel in response to elevations of intracellular calcium, increase airway fluid secretion, and promote mucus hydration and clearance.

Methods:

Methods: Study ET-TMEM-01 was a first-in-human, randomized, double-blind, placebo-controlled interventional study to assess the safety, tolerability, and pharmacokinetics of single (SAD) and multiple ascending doses (MAD) of inhaled nebulized GDC-6988 (ETD002) in healthy volunteers (NCT04488705). The study consisted of three parts: Part A evaluated single doses of GDC-6988 up to 150 mg, and Part B evaluated GDC-6988 up to 75 mg BID for up to 14 days. Part C was added after study initiation to explore the effect of pre-treatment with albuterol on changes in lung function observed during Part B, and consisted of albuterol pretreatment on Days 5-7 of a 7-day treatment period with 75 mg BID GDC-6988.

Results:

Results: Overall, 76 subjects received GDC-6988 or placebo (Part A = 36; Part B = 18; Part C = 8). All adverse events (AEs) were mild or moderate in severity. AEs reported in over 10% of subjects included headache (6 [12.5%] subjects in Part A; 4 [16.7%] subjects in Part B; none in Part C). In Part B, decreases in FEV1 of at least 10% from baseline to 30 minutes after at least one dose were seen in some subjects who received GDC-6988 (1 subject at 22.5 mg BID, 3 subjects at 45 mg BID, and 4 subjects at 75 mg BID), which generally resolved by the next predose measurement. Of these, two subjects receiving 75 mg GDC-6988 BID withdrew from study treatment due to an AE, one of moderate chest discomfort, and the other of pre-defined lung function stopping criteria, respectively. The AEs were associated with transient decreases in FEV1 of up to 17% and 21.7%, respectively that completely or mostly recovered within 4 hours. There was no apparent correlation between systemic exposure and change in FEV1. In Part C, FEV1 variations were again observed on Days 1-4; however, albuterol 200 µg pretreatment on study Days 5-7 mitigated the FEV1 decreases seen in Part B of the study (Figure 1). Key PK parameters of GDC-6988 Cmax and AUC increased with increasing doses, with relatively high variability (CV% of ~80% in AUC and Cmax). The Cmax and AUC were approximately dose proportional in the SAD cohorts. No clear accumulation was observed in MAD cohorts due to the relatively short elimination half-life. Co-administration of GDC-6988 with albuterol had little impact on the GDC-6988 PK parameters, but variability in the exposure-related parameters was reduced.

Conclusions:

Conclusions: GDC-6988 is generally safe and well-tolerated at doses of up to 75 mg BID by nebulized inhalation. Reductions in FEV1 are self-limited and can be mitigated with albuterol pre-treatment. As expected, systemic exposure levels of GDC-6988 are low. A Phase 1B study of GDC-6988 in healthy volunteers with a dry powder inhaler formulation is planned.

Acknowledgements:

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