Cisbio eBook - 21

Trends in Protein-Protein Interactions Research | Advantages May Place Peptides Ahead of Small-Molecule Drugs

one shown here (yellow), that may perform
better than small molecules in terms of potency
and selectivity.

Complement Immunotherapy
"With APL-2 we prevent the very first step of
complement deposition on cell surfaces," says
Cedric Francois, M.D., Ph.D., co-founder, CEO,
and president of Apellis Pharmaceuticals. A
key effort at Apellis involves the development
of complement immunotherapies, a strategy
that shows promise for treating autoimmune and inflammatory conditions in which
the complement cascade orchestrates the
When complement components are targeted,
complications may ensue because complement components are involved in many cellular
processes. "This is why there were a lot of fears
that inhibiting C3 may lead to unintended consequences," explains Dr. Francois.
APL-2, the lead molecule developed by Apellis, is
made of two synthetic cyclic peptides conjugated
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to a polyethylene glycol polymer. APL-2 binds
specifically to a pocket in C3 and C3b and inhibits
all three pathways of complement activation.
Using APL-2, scientists at Apellis developed two
clinical programs: a systemic program and a local
program. These programs, which are being run
in parallel at Apellis, are highly complementary,
maintains Dr. Francois, who adds that they are
both generating "very promising data."
In the systemic program, APL-2 is injected subcutaneously to inhibit C3 systemically, and the lead
indication is for paroxysmal nocturnal hematuria. "The systemic indication is a great proof of
concept, but the challenge is to make sure it is
safe," notes Dr. Francois.
In the local program, which was developed for
ophthalmological applications, a very small
amount of the therapeutic is injected into the
eye. "Safety is far less of a consideration for the
ophthalmological application, but establishing
efficacy is a much bigger hurdle," indicates
Dr. Francois.

The ophthalmological application of APL-2 is for
geographic atrophy, one of the two advanced
forms of macular degeneration, the other one
being wet age-related macular degeneration.
Geographic atrophy is characterized by the
progressive destruction of the retina starting
from the periphery. The areas of atrophy make
the retina appear like a map upon examination,
explaining the term given to this condition.
If the fovea is spared, which is typical of the initial
phase of the disease, visual acuity may remain
stable over time even though the visual function
progressively becomes impaired. However, at
advanced stages, once the fovea is affected, visual
acuity is lost dramatically over a very short time.
"The best analogy is with a forest fire," suggests
Dr. Francois. The lesion is initially localized to a
small area of the retina. "But eventually," Dr.
Francois points out, "the entire retina disappears."
Any therapy that could slow the rate of retinal
destruction would be highly beneficial.
"Because of that progression, for Phase III trials of

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