Saniona avslutade 2023 med att välja SAN2355 som den första kliniska kandidaten från sitt epilepsiprogram Kv7. Efter att framgångsrikt ha klarat av de kritiska stegen i kandidaturvalet och säkrat ett positivt utlåtande från det europeiska patentverket, kommer Saniona nu att avancera SAN2355 till preklinisk utveckling. BioStock pratade med Sanionas vd Thomas Feldthus för att få veta mer om denna milstolpe.

Saniona fokuserar på upptäckt och utveckling av läkemedel som modulerar jonkanaler. Bolagets epilepsipipeline inkluderar den fas II-klara läkemedelskandidaten SAN711, den prekliniska utvecklingskandidaten SAN2219 och nu även SAN2355 från Kv7-programmet.

En ny generation epilepsibehandlingar

I jakten på nya epilepsibehandlingar fokuserar Saniona och andra läkemedelbolag såsom Xenon Pharmaceuticals och Biohaven i allt högre grad på Kv7-kanaler i hjärnan. Saniona utvecklar en ny grupp av substanser som är utformade för att kringgå begränsningarna hos tidigare behandlingar och förbättra stabilitet, selektivitet och verkningsmekanism för ökad effektivitet och tolerans. Framför allt adresserar SAN2355 den potentiellt livshotande biverkningen urinretention samt CNS-biverkningar som är associerade med icke-selektiva Kv7-aktivatorer. Läs mer här.

Når milstolpe med SAN2355

I november 2023 initierade Saniona kandidaturvalsfasen med en subtypselektiv frontrunner-molekyl från lead optimization-programmet med Kv7. Förra veckan kommunicerade Saniona att den nya epilepsikandidaten SAN2355 har passerat alla kritiska steg i denna process och nu är redo för preklinisk utveckling.

Vd kommenterar

BioStock kontaktade Sanionas vd Thomas Feldthus för att få veta mer om SAN2355 och vilken framtid han ser för kandidaten.

How does SAN2355’s subtype selectivity among Kv7 channels set it apart, and what advantages does it offer in terms of efficacy and tolerability for treating epilepsy compared to non-selective activators?

– The Kv7 channels comprise a family of five members, Kv7.1-Kv7.5.

– SAN2355 is a selective activator of the Kv7.2 and Kv7.3 channels which are localized in the brain and comprise the targets for treatment of epilepsy. We believe that Saniona is the first company, which has been able to produce a compound with this unique profile. We expect that SAN2355 will be more effective than competing pipeline programs because it can be given in higher doses, and we expect that patients will experience less side effects on comparable dose levels.

– All competing pipeline programs appear to be unselective activators of four Kv7 channels, Kv7.2 – Kv7.5, which results in dose limiting side effects and considerable dropouts from the clinical studies. Kv7.4 channels are expressed in various cells in the body including the bladder so activating Kv7.4 may result in life threatening urinary retention in some patients. Kv7.5 channels are also expressed in the brain and are likely contributing to the dose limiting CNS side effects of competing programs in development.

Can you elaborate on the critical steps SAN2355 has successfully passed in the candidate selection process, and what factors contribute to its readiness for preclinical development?

– The candidate selection process comprises a battery of test and analysis, which is designed to de-risk the program and ensure that the lead candidate has drug-like characteristics before initiating expensive preclinical IND/CTA enabling studies. SAN2355 has now successfully passed all these tests which can be divided into:

• In vivo pharmacology (efficacy)
• Drug metabolism, distribution, pharmacokinetics and elimination including human dose estimation
• Safety pharmacology and toxicology (such as AMES test (carcinogenic risk) and hERG screens (negative cardiac effects), off-target screen (other side effect risk) and MTD studies (maximum tolerated dose)
• Preliminary establishment of large-scale manufacture of drug substance and formulation (CMC activities)

– Based on our candidate selection process, we have concluded that SAN2355 represents a clinical candidate with a differentiated pharmacology profile, which potentially offers better seizure control and improved tolerability than competing nonselective Kv7 pipeline programs.

Considering the commercial interest in the Kv7 program, what aspects of SAN2355 will increase its attractiveness, and how do you foresee its potential impact on the epilepsy treatment landscape?

– We see SAN2355 as a second generation of Kv7 activators which may have a significant impact on the treatment modality for patients with resistant focal and generalized seizures as well as paediatric patients with seizures caused by genetic mutations in the Kv7 channels.

Given the withdrawal of the non-selective Kv7 activator retigabine from the market, how does SAN2355 address or mitigate the side effects that led to the withdrawal?

– Retigabine is a non-selective Kv7 activator, which has been withdrawn from the market due to discolouring of the retina and certain other tissues due to unstable and reactive chemistry (aniline-moiety). SAN2355 is a selective Kv7 activator based on novel chemistry without the safety liabilities associated with the aniline-moiety of retigabine and XEN1101, the leading competing pipeline program from Xenon.

What patient populations do you anticipate benefiting most from this new candidate, both in terms of adult and childhood epilepsies?

– Kv7 is a validated target for treatment of adult patients with resistant focal onset seizures. It is a very large market. There are around 1.2 million patients with resistant focal onset seizures in the U.S. and Europe combined. There are no Kv7 drugs on the market today. But there are at least two promising Kv7 candidates in clinical development, which most likely will reach the market several years before the launch of SAN2355. Both compounds are expected to be highly efficacious and obtain peak sales of more than 1 BUSD. However, these drugs are non-selective Kv7 activators.

– A large fraction of patients may stop treatment due to side effects and/or not obtain seizure freedom due to dose limiting toxicity. These patients may be the initial target for SAN2355. In the long term SAN2355 may gain market share in the entire resistant patient population due to better efficacy and improved tolerability.

– Kv7 is also a very relevant target for treatment of many paediatric patients since genetic mutations in the Kv7.2/Kv7.3 channels are among the most common reasons for childhood epilepsy. This market could be wide open for SAN2355. Thus, previous small studies with retigabine in paediatric patients indicate that children are much more sensitive to activation of the Kv7.4 channels than adults leading to severe urinary retention, which was one of the known adverse effects caused by treatment with the unselective drug retigabine in adults. It should be noted that Xenon has recently discontinued development of retigabine for paediatric patients – although for undisclosed reasons.

Finally, what future potential do you see in SAN2355?

– SAN2355 has a clear differentiation to competing pipeline programs and represents a new generation of Kv7 activators for the treatment of resistant adult patients and pediatric patients with genetic mutations in the Kv7 channels. Each market segment represents a billion-dollar market opportunity.

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