Wave Initiates Trial of Investigational Antisense Oligonucleotide Against Huntington’s Disease

At the EHDN 2021 Remote Meeting held last week, Cambridge, MA-based biotech Wave Life Sciences announced the initiation of dosing in its Phase 1b/2a trial that evaluates WVE-003, its investigational drug against Huntington’s disease (HD).

Huntington’s Disease

HD is a progressive neurological disorder characterized by selective loss of neurons in the striatum and cortex. This leads to uncontrolled movements, psychiatric problems, and loss of cognition in patients. HD is caused by the mutations either inherited or spontaneously acquired on the huntingtin (HTT) gene.

According to statistics, approximately 30,000 people in the US have symptomatic HD, and more than 200,000 are at risk for developing the disease. So far, there are no approved disease-modifying therapies. However, current treatments include antipsychotic drugs, antidepressants, and tranquilizers which provide symptomatic relief.

Although the exact function of the wild-type HTT (wtHTT) protein is under investigation, it is critical for neuronal function. HD occurs when the expansion of cytosine-adenine-guanine (CAG) triplet repeats gives rise to the accumulation of mutant HTT (mHTT) protein.

Allele-Selective Approach Fuelled by Novel PN Chemistry

WVE-003 is a stereopure antisense oligonucleotide designed to target SNP3, a single nucleotide polymorphism on the mHTT allele. Therefore, the mHTT protein is selectively lowered, sparing the healthy wtHTT protein.

Wave is the only company with an allele-selective clinical program in HD. This approach is guided by the recognition that, in addition to a gain of function of the mHTT protein, people with HD have lost one copy of the wtHTT allele, leaving them with a smaller protective reservoir of healthy protein than unaffected individuals.

WVE-003 incorporates Wave’s novel PN backbone chemistry modifications (PN chemistry), which demonstrated enhanced potency, exposure, and durability in preclinical studies as compared to Wave’s first-generation chemistry.

“WVE-003 reflects the significant evolution of our chemistry and the many learnings gained from our first-generation clinical programs,” said Michael Panzara, MD, MPH, CMO, and Head of Therapeutics Discovery and Development at Wave Life Sciences.

“Compared to traditional PS/PO modifications, introducing the novel PN modifications has changed the properties of our candidates for the better,” Dr. Panzara told GeneOnline.

“In our preclinical programs for ALS and FTD, we have observed that mice models have durable effects for up to six months. We have also seen those durable effects in the transgenic mice of our HD model where mHTT protein is selectively lowered while preserving the wtHTT protein. So, the platform evolution over the past several years has brought us to a place where we have this PS/PO/PN approach to these diseases, which we believe will enhance the clinical benefit,” he added.

Positive Preclinical Data

In preclinical studies, WVE-003 demonstrated dose-dependent and selective reduction of mHTT mRNA in vitro and potent and durable knockdown of mHTT mRNA in vivo in both the cortex and striatum. Data from several preclinical models evaluating pharmacokinetic to pharmacodynamic relationships for WVE-003 have informed the starting dose for the SELECT-HD trial.

SELECT-HD is designed to be adaptive with dose escalation, and dosing frequency is guided by an independent committee, thereby enabling faster optimization of dosing and decision-making on the next steps for WVE-003.

“Our enthusiasm for this program is bolstered by a compelling set of preclinical data that demonstrated selectivity, potency, and durability of WVE-003 with effects in relevant brain regions. Further, emerging data continue to indicate that a fundamental requirement for clinical success in HD treatment will be the need to preserve wild-type HTT protein, supporting our allele-selective approach to mutant HTT protein reduction,” Dr. Panzara added.

Wave Life Sciences was featured as one of GeneOnline’s list of 6 Companies leading the resurgence in RNA editing R&D.

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Author

Rajaneesh K. Gopinath