After encouraging results showing rapid reversal of stress-induced depression, Saniona selects SAN2465 as a clinical candidate for major depressive disorder. The announcement comes less than a week after Saniona chose SAN2355 as the first clinical candidate from its Kv7 epilepsy program. BioStock reached out to Saniona’s CEO Thomas Feldthus for a comment.

Saniona’s epilepsy pipeline includes the phase II ready asset SAN711, the preclinical compounds SAN2219 and SAN2355. On December 27^th 2023, Saniona selected the new epilepsy candidate SAN2355 from its Kv7 program. Read a comment from the CEO Thomas Feldthus here.

The Danish biotech has three clinical programmes outside the epilepsy area positioned for partnering. Tesomet is ready for phase IIb in rare eating disorders, while SAN903 is ready for phase I in inflammatory bowel disease. The most advanced candidate, tesofensine, has progressed towards regulatory approval for treating obesity in Mexico by Saniona’s partner Medix.

Saniona also has a partnership with Boehringer Ingelheim focusing on cognitive impairment associated with schizophrenia. On December 18^th last year, the partnership was extended for up to two years. Saniona may receive up to 76,5 million Euro in milestone payments as well as royalties on worldwide net sales of resulting products under the collaboration.

Milestone reached with SAN2465

Earlier this week, Saniona announced the selection of its proprietary lead compound SAN2465 as a clinical candidate for major depressive disorder. The decision follows encouraging results obtained from a rodent model, specifically the chronic mild stress model of depression. SAN2465 can now proceed to preclinical development as a rapid-acting antidepressant in collaboration with a partner.

A significant medical need

Conventional pharmacologic treatments for major depressive disorders include selective serotonin reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants. These therapies work through modulation of the same (monoaminergic) system and exhibit in general delayed clinical responses and low remission rates. Further, more than 30 per cent of the patients do not respond adequately, leading to treatment-resistant depression.

Saniona’s data suggest that SAN2465 may induce rapid antidepressant effects similar to those observed with Johnson & Johnson’s Spravato (esketamine). Despite the FDA approval of esketamine in 2019 as the first fast-acting prescription antidepressant, it is only available through a restricted program since being associated with significant risks. All taken together, there is a significant medical need for improved fast-acting safe treatment options with a different mode of action.

“Two new drug candidates in one year would be challenging for many large pharmaceutical companies. In our case, we have increased our pre-clinical/clinical pipeline of ion channel modulators from three to five candidates in one year” – Thomas Feldthus, vd Saniona

Comments from the CEO

BioStock contacted Saniona’s CEO Thomas Feldthus, who wants to position SAN2465 as a first-in-class rapid-acting antidepressant without the significant adverse effects associated with esketamine.

Thomas, can you elaborate on the specific advantages of SAN2465 as a potential rapid-acting antidepressant and how it addresses the limitations seen in conventional therapies like esketamine?

– As mentioned in our press release, the conventional therapies for major depressive disorders all rely on modulating the monoaminergic system. They have the same shortfalls with a delayed onset and low remission rate. It may take 4-6 weeks before patients experience an effect. If they experience a fallback of symptoms during treatment with the prescribed medicine, it may take several weeks before the new medicine works. During these periods, patients have increased suicidal risk. Moreover, there is a risk of cross resistance since conventional therapies have a common mode of action. There is, therefore, a major medical need for novel and improved antidepressant treatments with different mode of action and with a rapid onset.

How does the mechanism of action of esketamine differ from conventional antidepressants?

– Esketamine is a version of the NMDA antagonist ketamine, which was synthesised in the 1960s and introduced as an anaesthetic for surgical procedures in the 1970s. In 2000, it was discovered that ketamine had a remarkably rapid anti-depressive effect based on a different mode of action. This discovery has been described as the single most important advance in the treatment of depression for more than 50 years.

– The mechanism of action for depression is not fully understood. However, it is generally believed that the anti-depressive effect is caused by a blockade of NMDA receptors, which in turn modulate a variety of downstream signalling pathways to influence neurotransmission in the limbic system of the brain. Esketamine was developed and subsequently approved for the treatment of depression in the U.S. and EU in 2019.

– Esketamine is associated with significant risks, including sedation, dissociation, respiratory depression, and abuse and misuse. Therefore, esketamine is only available through a restricted program called the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) Program.

– Therefore, there is a significant medical need for improved safe treatment options with rapid-onset and clinical response devoid of the use limitations associated with esketamine. This has led to significant interest and research for other and perhaps better tolerated NMDA receptor antagonists, so far without success.

How does the mechanism of action of SAN2465 differ from conventional antidepressant drugs and esketamine, and what potential does it hold for becoming a first-in-class treatment?

– SAN2465 is a highly potent and selective negative allosteric modulator of GABAA α5, which is a completely different mechanism than conventional therapies.

– Literature evidence suggests that such a mechanism could be useful as a new antidepressant principle since the GABA a5 target is involved in several downstream signalling pathways of esketamine. Importantly, as opposed to esketamine, negative modulation of GABAA α5 receptors is not anticipated to lead to significant adverse effects, as the expression of these receptors is more localized and mainly restricted to limbic areas.

– We have now tested SAN2465 in the gold standard animal model for major depressive disorder together with one of the most recognised pioneers and experts in the field, Professor Mariusz Papp. In this model, SAN2465 demonstrated rapid and sustained reversal of chronic stress-induced depressive-like symptoms, including anhedonia, anxiety, and cognitive impairment. The onset and robustness of the antidepressive effect were similar to ketamine, which was used as a positive control in this study.

– Consequently, SAN2465 represents a new innovative approach for the treatment of major depressive disorder, which differs substantially from conventional antidepressant drugs in its mechanism of action, and which has the potential to become a first-in-class rapid-acting antidepressant without the significant adverse effects associated with esketamine.

Given the promising rodent model results, what is the timeline for the preclinical development of SAN2465, and what milestones do you anticipate?

– SAN2465 is set for preclinical development, which typically takes about 18 months. After, this you can start Phase 1 clinical studies.

– It is a high-quality program, which we originally developed together with a pharmaceutical partner for another indication. To this point, there has been synthesised thousands of compounds and probably invested more than 15 MUSD over a 10-year period. Furthermore, SAN2465 has been through extensive testing during the candidate selection process. It is a selective, highly potent (picomolar range affinity) and well characterized drug candidate, which appears to be very well tolerated in preliminary toxicology studies.

– We knew that we had a very valuable asset if we could identify an indication for this program. During 2023, we have tested it for various indications. Obviously, we got very excited when we learned about the results in major depressive disorders.

Considering the significant medical need for improved and safer treatment options, how could SAN2465 fill this gap?

– There is a substantial medical need within major depressive disorders. Approximately 280 million people globally suffer from depressive disorders, and it stands as one of the leading causes of disability. Existing conventional therapies show delayed clinical responses and more than 30% do not respond adequately, leading to treatment resistant depression.

– The introduction of esketamine as a rapid-acting antidepressant based on a new mode of action is a breakthrough for treatment resistant depression. However, the use is significantly restricted by the severe side effects of esketamine.

– SAN2465 may be useful for treatment-resistant patients. It may be useful as a fast onset treatment for all patients during the first 4-6 weeks of treatment where patients do not experience an effect from conventional therapies. Ultimately, it may be used in first line. The final positioning will be determined during the clinical development and subsequent use. It is a high-quality drug candidate based on a novel mode of action, which appears to be well tolerated in preliminary toxicology studies. It has the potential to meet the substantial medical need within major depressive disorders.

What partnerships or collaborations are being explored to advance its development?

– We are focusing on epilepsy. Therefore, we plan to develop this compound in collaboration with a partner. There are many companies interested in the field, both biotech companies and major pharmaceutical companies. It is still early days, and we are looking forward to sharing the results with potential partners. It would probably be a worldwide license deal if developed together with a major pharmaceutical company.

You’ve selected two clinical candidates in less than a week. Will the proceeds potentially generated from the upcoming rights issue (scheduled to commence on January 22^nd) be sufficient to support the preclinical development of these newly chosen assets?

– Yes, it is a quite remarkable progress. You don’t see that often. Two new drug candidates in one year would be challenging for many large pharmaceutical companies. In our case, we have increased our pre-clinical/clinical pipeline of ion channel modulators from three to five candidates in one year.

– The selection of the SAN2355 for epilepsy is based on strong teamwork for 19 months following the initiation of lead optimization in August 2022. It is a highly selective Kv7.2/Kv7.3 activator with a clear differentiation to competing pipeline programs. We believe that we are the first company which has been able to produce a compound with this profile. It is a very difficult task. We have tried to do this for decades and we know that other companies have tried too. In 2022, we got some promising results and decided to enter the lead optimization phase.

– We reached some additional breakthroughs during spring 2023 and decided in the fall to prepare a front-runner for candidate selection. The front-runner had a perfect profile and looked very promising in animal models. The question was whether it also had drug-like characteristics. It is difficult to get the arms down for our team when this proved to be the case.

– The situation was different when it came to the selection of SAN2465 for major depression disorder. We had a highly selective and potent compound with drug-like characteristics. But we had no indication to use it for. This task is of course just as important. And it can prove to be just as difficult to solve. I will dedicate this achievement to our CSO, Karin Sandager Nielsen.

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