Relationship Between Central and Peripheral SMN Protein Increase Upon Treatment with RO7034067 (RG7916) (S46.007)

Objective: To assess tissue distribution and effect of RO7034067 (RG7916) on survival of motor neuron (SMN) protein expression in animal models of spinal muscular atrophy (SMA).

Background: RO7034067 is an oral, small-molecule SMN2 pre-mRNA splicing modifier that distributes into CNS and peripheral tissues. RO7034067 was designed to penetrate the CNS avoiding interaction with human MDR1, a transport protein that restricts brain penetration. RO7034067 is under investigation in SUNFISH, FIREFISH and JEWELFISH.

Design/Methods: Distribution of RO7034067 into brain and CSF was assessed in two SMA transgenic mouse models (Δ7 and C/C-allele), rats and cynomolgus monkeys after single and repeated daily oral doses, up to 39 weeks. SMN protein levels in blood, brain and muscle of SMA transgenic mice were monitored.

Results: Total drug levels were similar in plasma, muscle and brain of mice, rats and monkeys. CSF levels reflected those of free, non-bound compound in plasma. For example, oral dosing of RO7034067 at 3 mg/kg/day for 7 days in monkeys (n=2), total plasma concentrations (794 ng/ml) matched brain (783 ng/g) and muscle (668 ng/g) concentrations, whereas CSF drug level were within the same range of free compound concentration in plasma. This tissue distribution was maintained in monkeys receiving RO7034067 daily for 39 weeks.

SMN protein level increase in brain and muscle of SMA transgenic mice was dose-dependent. For example, 7 days’ dosing in Δ7 mice (n=7) resulted in a similar increase in the SMN protein levels in brain and muscle (0.1 mg/kg/day: brain 28%, muscle 32%; 1 mg/kg/day, brain 206%, muscle 210%). SMN2 splicing modifiers with structural similarities to RO7034067 showed a parallel SMN protein increase in both brain and blood of SMA mice.

Conclusions: PK/PD relationships in animal models imply that SMN protein increases seen in patients’ blood following RO7034067 treatment are expected to yield parallel SMN protein increase in CNS and muscle.

Study Supported by: Sponsored by F. Hoffmann-La Roche

Disclosure: Dr. Poirier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F.Hoffmann-La Roche employee. Dr. Weetall has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Weetall holds stock and/or stock options in I have stock in PTC Therapeutics, Inc., which sponsored research in which Dr. Weetall was involved as an investigator. Dr. Weetall has received research support from PTC Therapeutics, Inc. Dr. Ratni has nothing to disclose. Dr. Heim has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Naryshkin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Paushkin has nothing to disclose. Dr. Mueller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche, Basel, Switzerland. Dr. Mueller holds stock and/or stock options in F. Hoffmann-La Roche, Basel, Switzerland.