Rationale:
Lafora disease (LD) is severe genetic epilepsy and fatal childhood dementia. LD is caused by genetic variants in the
EPM2A or
EPM2B genes encoding the enzymes laforin (a dual specificity phosphatase) and malin (a ubiquitin E3 ligase), respectively, whose dysfunction creates insoluble glycogen aggregates of polyglucosan called Lafora Bodies (LBs). Genetic mouse models have demonstrated that these LBs are the principal driver of neurological disease and LD pathology (Turnbull et al. 2016).
Methods:
VAL-1221 (Fab-GAA) is a fusion protein incorporating an enzyme and targeting antibody designed to provide the following: 1) enhanced tissue delivery, 2) novel intracellular uptake, and 3) targeted glycogen degradation. Dual functionality allows VAL-1221 the unique capability of clearing cytoplasmic LBs. In LD mice, VAL-1221 treatments cleared LBs and corrected metabolism (manuscript in submission). Similar mechanistic findings were published with an earlier research fusion (Brewer et al. 2019). Importantly, both instances demonstrated that antibody-enzyme targeting was crucial for LD efficacy, as both Amylase- and alpha-glucosidase-alone were found to be ineffective in LD mouse models (Brewer et al. 2019 and third party manuscript in preparation). VAL-1221 previously demonstrated promise in a former Pompe Phase I/II trial (NCT02898753). However, more clinical studies are needed to validate the unique VAL-1221 opportunity to treat LD and other related polyglucosan diseases (PGDs).
Results:
Currently ten LD patients are being treated with VAL-1221 utilizing intravenously-infused 20mg/kg dosing every other week under a prospective U.S. Lafora Expanded Access Protocol (LEAP) and via International Compassionate Use. Positive safety and promising case study findings have been reported by both caregivers and treating physicians. Six month interim evaluations including one year findings on a couple of patients will be available later this year. At baseline, these LD patients have been prospectively evaluated by clinical assessment and medical history. Seizure diary recordings including a minimum 28-day baseline, EEG measures, cognitive assessments, and motor functions have been included under the Lafora Expanded Access Protocol (LEAP) to best align with future planned U.S. IND and European-grant funded Phase II trials.
Conclusions:
VAL-1221 is a promising therapeutic candidate for Lafora disease and other related PGDs. The development of joint safety and efficacy databases from ongoing treatments will be very informative as more pivotal studies are initiated. Future research detection of VAL-1221 in treated patient CSF and combined analysis of plasma and CSF metabolic biomarkers will seek to further establish on-target mechanism of action. Together, these findings will seek to demonstrate a clear functional connection between targeted glycogen degradation and positive clinical benefit for VAL-1221 treated LD patients.
Funding:
Parasail is funded via personal investment, foundation support, and other third party donations. Efforts are underway to seek additional partnerships and larger financing for further development.