Kallikrein inhibition has largely disappointed in its first clinical use, hereditary angioedema, but an emerging pipeline of projects suggests that it could yet have some value in eye disease.
This approach now has an endorsement from Merck & Co, which has picked up Kalvista Pharmaceuticals’ phase I project KVD001 for $37m up front plus an equity stake to advance it to phase II in diabetic macular oedema (DME) before the end of the year. Kalvista is not alone in this chase – four preclinical projects are being readied in eye disease, while it would not be surprising to see the kallikrein veteran Biocryst turn its attention to this new use now that big pharma has put money on the table.
Making more than HAE
In hereditary angioedema (HAE), inhibiting plasma kallikrein has the effect of blocking inflammatory pathways and treating acute outbreaks. Kalbitor has been constrained by its black box warning for anaphylaxis and the shift to preventive care. This is a fate that Shire will hope it can avoid with the first antibody to block kallikrein, lanadelumab, which so far has not been tested beyond HAE.
In DME, an inflammatory response is also thought to lead to a breakdown of blood vessels that causes fluid to collect in the eye. Because of the similarities with wet age-related macular degeneration, VEGF inhibitors like Lucentis are indicated for DME, and Eylea is used off-label – however, a significant share of DME patients do not respond.
Like the VEGF agents, KVD001 is an intravitreal injection. It has completed a phase I trial in 14 patients testing safety, plasma levels and improvements in visual acuity. Kalvista reported a numerical improvement in eyesight, with a mean change in visual acuity of approximately four letters at 84 days following a single dose, although this is far too small a patient group from which to draw broad conclusions.
Investigators reported two adverse events: one case of mild eye inflammation and one severe increase in intraocular pressure, the first considered possibly related to and the second probably related to KVD001. Both were in the medium of three doses tested.
The Merck-backed phase II expected to begin later this year will involve four injections over three months in patients who have not responded to anti-VEGF agents, and will include a control group. Improvement in visual acuity will be the primary endpoint, and results could come by the end of 2018.
Approaching the clinic
But Kalvista does not look like it will be alone.Thrombogenics has made a full commitment to eye disease, especially since regaining non-US rights to Jetrea from Novartis. THR-317 and THR-409, respectively an antiplacental growth factor and an alpha-2 antiplasmin blocker, are already in the clinic in diabetic retinopathy.
|Kallikrein inhibitors in DME|
|Phase I||KVD001||Kalvista Pharmaceuticals|
|Preclinical||Kallikrein Inhibitors Program||Verseon|
Thus, the kallikrein inhibitor THR-149, licensed from Bicycle Therapeutics, looks like a earlier shot on goal for the Belgian group, as it is expected to enter the clinic in 2018; earlier this year, Thrombogenics said it had begun formal toxicology studies.
Verseon is trying a different route, using eye drops rather than intravitreal injections – the latter risks inflammation, infection and tissue damage, but the former could have more difficulty reaching the site of inflammation and risks greater systemic exposure.
Systemic exposure is also a risk with Activesite Pharmaceuticals’s kallikrein inhibitor pill, about which the company has not reported data since 2011. As a sign of biopharma interest in this field, however, Antriabio licensed in Activesite’s kallikrein inhibitors in August, with DME mentioned prominently as a disease target.
Antriabio’s deal raises the question of Biocryst’s next move. It has the most advanced kallikrein inhibitor in the form of BCX7353 in phase II, and although its work is in HAE, the recent activity must have it thinking about a pivot into eye disease. And the $37m in Merck cash cannot have escaped Biocryst’s notice.