CERE-120 (AAV2-neurturin)

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Ceregene (sponsor), with Michael J. Fox Foundation funding for the first trial. Sangamo Biosciences bought Ceregene in October 2013. Marks, Bartus, Siffert and colleagues (Lancet Neurology 2010); C. Warren Olanow, Raymond Bartus, Thomas Baumann and colleagues (Annals of Neurology 2015).

What happened

Neurturin is a growth factor that works through the same receptor as GDNF. CERE-120 is a harmless virus (AAV2) carrying the neurturin gene. The aim was to make surviving dopamine neurons make their own growth factor for years, avoiding the pump problems seen with GDNF (landmark 146). The surgical delivery follows the approach shown in AADC gene therapy.

• Trial 1 (2010). Double-blind, sham-surgery-controlled Phase 2 (NCT00400634). 58 people with advanced disease at nine US sites, enrolled Dec 2006–Nov 2008, 2:1 to CERE-120 (5.4×10¹¹ vector genomes, both putamens) or sham. Main measure: off-medication motor score at 12 months. Difference −0.31 points (95% CI −5.58 to 4.97, p=0.91): no effect. Serious adverse events 13 of 38 treated and 4 of 20 sham. Tumours were found in 3 treated and 2 sham people. The authors said a benefit from also targeting the substantia nigra and longer follow-up should still be tested.
• Why it may have failed. Autopsy of two treated patients found neurturin covered only about 15% of the putamen and rarely reached the substantia nigra cell bodies, perhaps because transport along the nerve fibres is impaired in advanced disease (Bartus et al., Mov Disord 2011).
• Trial 2 (2015). Same idea, now also injected into the substantia nigra (2.0×10¹¹ vg) as well as the putamen (1.0×10¹² vg). 51 people enrolled (the registry, NCT00985517, lists 57 and began Oct 2009), sham-controlled, 15–24 months. Main measure: off-medication motor score. Change −7.0 versus −5.2 points on sham (p=0.515). Two people had brain bleeds with transient symptoms. No clinically meaningful adverse events were attributed to the drug. The authors concluded it was not superior to sham surgery.

Why it moved us toward a cure

It showed that getting a growth-factor gene into the right cells at the right level is hard. Both groups in trial 2 improved by 5 to 7 points, so sham-controlled designs are needed. It prepared the ground for the newer GDNF gene therapy (landmark 39), which uses a different gene, a different dose and delivery plan, and a milder disease stage.

Outcome

Dead end for this product. Ceregene reported in April 2013 that the second trial missed its primary endpoint (seen only via a search summary of Sangamo filings), and Sangamo bought the company that October; the registry now lists Sangamo as sponsor of trial 2, which completed in 2017. No later development was found.

Sources

• Marks et al., Lancet Neurol 2010;9:1164–1172, DOI 10.1016/S1474-4422(10)70254-4 (abstract record)
• Warren Olanow et al., Ann Neurol 2015;78:248–257, DOI 10.1002/ana.24436 (abstract record)
• Registry: NCT00400634 · NCT00985517 · Sangamo 10-K for 2013 on the Ceregene purchase
• Bartus et al., Mov Disord 2011;26:27–36, DOI 10.1002/mds.23442, PMC6333467
• Not yet verified: the 51 versus 57 enrolment gap; the 15% putamen coverage figure (from the Bartus 2011 autopsy report, not re-read); the 18-month sub-analysis; the exact April 2013 Ceregene announcement (seen only via a search summary of Sangamo filings).