Fresh off its merger with Graphite Bio, Inc., LENZ Therapeutics, Inc. (LENZ) announced the release of positive topline data from the phase 3 CLARITY 1 and 2 trials evaluating its lead product candidate LNZ100 (1.75% aceclidine).
Let’s start with LENZ.
Based in San Diego, California, LENZ is a late-stage biopharmaceutical company that is developing and potentially commercializing innovative therapies to improve vision—with a major focus on two investigational therapies for presbyopia.
Note: LENZ Therapeutics and Graphite merged in March 2024 under one name (LENZ) to advance these presbyopic therapies, formulated as eye drops:
- LNZ100 ((1.75% aceclidine; more details below)
- LNZ101 (1.75% aceclidine and brimonidine)
Now LNZ100.
Similar to LNZ101, LNZ100 is formulated as preservative-free, single-use, once-daily eye drops intended to treat presbyopia.
Aceclidine refresh: This small-molecule muscarinic acetylcholine receptor agonist can cause miosis, which might result in a “pinhole” effect to improve near vision and prevent a myopic shift.
Note: In Europe, aceclidine has been indicated for the treatment of open-angle glaucoma (OAG) for over a half century.
Before we get to these phase 3 studies … what did phase 2 find?
The phase 2 INSIGHT trial (NCT05294328) previously reported positive topline data on both LNZ100 and LNZ101.
Each therapy met the primary endpoints of a 3-line or greater improvement in visual acuity (VA) without losing 1-line or more in distance VA at 1 hour:
- LNZ100: 70% of treated patients (p<0.0001)
- LNZ101: 56% of treated patients (p<0.0001)
The formulations also maintained an average pupil size of 1.5-2 mm for 10 hours (also a biomarker of efficacy):
- LNZ100: 37% of treated patients
- LNZ101: 48% of treated patients
Gotcha. Now talk about these phase 3 studies.
Originally initiated in December 2022, the CLARITY program consists of three double-masked, randomized, U.S.-based, multi-center, safety/efficacy trials to further evaluate LNZ100 and LNZ101 for the treatment of presbyopia.
Zeroing in on these phase 3, 6-week efficacy trials, these include:
- CLARITY 1 for LNZ100 (NCT05656027)
- CLARITY 2 safety study (NCT05753189)
Details, please
Together, the studies enrolled a total of 1,059 participants (aged 45 to 75) with a refractive range of 4.0D spherical equivalent (SE) to +1.0D SE with subjects who previously had LASIK surgery or were pseudophakes.
The setup: Patients were randomized into three groups to receive bilateral doses of:
- Group 1: LNZ101
- Group 2: Placebo
- Group 3: LNZ100
And the outcome measures?
Just one was established: the percentage of participants who achieved three-lines or greater improvement in best-corrected distance visual acuity (BCDVA) at near without losing one-line (5 letters or more of distance vision) at 3 hours post-treatment.
Now this topline data.
Per LENZ, LNZ100 achieved all primary and secondary near-vision improvement endpoints in both the CLARITY 1 and CLARITY 2 trials.
Give me some numbers.
At 30 minutes post-treatment:
- CLARITY 1
- 72% and 87% of participants achieved three- and two-lines or greater improvement, respectively
- CLARITY 2
- 71% and 91% of participants achieved three- and two-lines or greater improvement, respectively
How about 3 hours (the primary endpoint)?
- CLARITY 1
- 64% and 83% of participants achieved three- and two-lines or greater improvement, respectively
- CLARITY 2
- 71% and 91% of participants achieved three- and two-lines or greater improvement, respectively
And at 10 hours (long duration)?
- CLARITY 1
- 27% and 61% of participants achieved three- and two-lines or greater improvement, respectively
- CLARITY 2
- 40% and 69% of participants achieved three- and two-lines or greater improvement, respectively
How was near vision improvement overall?
Across both trials throughout the 4-week study timeframe, “near vision improvement was reproducible and consistent,” the company reported.
Give me more LNZ100-specific data.
In CLARITY 2, 95% of LNZ100-treated participants achieved “clinically meaningful two-lines or greater improvement (p<0.0001) at 1-hour post-treatment.”
Further, LNZ100 demonstrated statistically significant (p<0.0001) “improvement of 2-4 letters on distance vision in normal light and no negative impact to distance vision in low light at all time points.”
That sounds promising… any adverse events?
Just a few… but overall, LNZ100 was noted as being well-tolerated with no treatment-related serious adverse events (AEs).
Reported AEs (occurring with an incidence of +5%) were 100% mild and included:
- Instillation site irritation
- Visual impairment
- Hyperemia
- Headaches (mild in 89% of participants)
Did the participants rate their vision improvement?
Yes, actually… 90% of the 223 LNZ100-treated participants who were given a survey reported “they noticed an improvement in their near vision.”
Additionally:
- 75% reported they would want to continue use of the drops following they study period
- 81% of these respondents stated they expected to use the drops 4-7 days a week
Gotcha. So what’s next?
LENZ reported that, based on these topline results, a new drug application (NDA) submission to the FDA for LNZ100 is anticipated by mid-2024… So stay tuned for additional data until then!