Tackling pain and mental health with plant-based medicines

Plant-based concept

DDW Editor Reece Armstrong speaks to Michael Krogh Jensen, Co-founder and CEO of Biomia, about developing plant-based medicines and what recent investment and support from the Bio Studio programme means for its pipeline.

RA: How has being part of the Bio Studio programme helped you develop your pipeline?

MJ: The Bio Studio programme has offered Biomia a ‘cloud’ of key opinion leaders providing constructive feedback and authoritative direction on our technology, working hypothesis, business models, budget, and timeline. This has been instrumental for us to critically assess where to play. Secondly, the programme has supported a focus on scientific excellence, which enabled us to release our study on the manufacturing of Velban from our engineered yeast cell factories as a proof-of- concept documenting Biomia’s biosynthesis platform. To this end, a grant of $3 million offered in the Bio Studio programme to mature a technology for ‘platform-market-fit’ is a unique opportunity for translational projects. Lastly, the environment at the BioInnovation Studio (BII) is in general a very stimulating and supportive start-up environment, enabling our team to mature both scientifically, professionally, as well as personally.

RA: Biomia is developing drug candidates for pain, addiction and mental health conditions. What are some of the historical challenges with these drugs?

MJ: Indeed, for all three health indications there are challenges with respect to adverse effects and the therapeutic targets. For current opioid-based analgesics, unwanted side effects include respiratory depression and nausea, as well as build-up of tolerance, while at the same time being highly addictive themselves. Furthermore, opiate- based medicines are often not effective against neuropathic pain. For antipsychotics, adverse effects include movement disorder, compromised immunity, body weight gain, and sleep disorders. Also, most second- generation antipsychotics have delayed onset, which may influence patient adherence. Lastly, for treatment of substance use disorders, few pipeline drugs are currently undergoing clinical trials, yet those in trial only address the withdrawal symptoms but not the underlying reward circuitry and the cravings.

RA: What advantages does a plant-based approach bring to drug development?

MJ: From the first known reference to medicinal use of plants on a Mesoptamian clay tablet written during the third millennium BC to the FDA approval of the blockbuster anticancer drug Taxol in the 1990s, natural products from plants have been at the forefront of efforts to overcome human diseases, such as cancers, hypertension, and pain. As such, the link between plant natural products and indication (or drug target) is often well established.

Additionally, plants are excellent chemists harnessing enzymes for sourcing bioactive drug leads with complex stereocenters and regioselective modifications which can then be considered for further development using semi- synthesis or biocatalysis.

RA: What opportunity is there for better treatments in pain and mental health conditions?

MJ: Besides addressing unmet needs and adverse effects, the sheer numbers of patients suffering from pain and mental health conditions such as schizophrenia and addiction are overwhelming. For instance, if we are looking at pain, NIH estimates up to 10% of the world population to suffer from neuropathic pain. For mental health conditions, according to the WHO, schizophrenia occurs in around one in 200 adults, and is regarded the most impairing of all mental health conditions with a reduced lifespan of 10 to 20 years compared to the general population. Furthermore, in terms of addiction, 178 million people worldwide suffer from a substance abuse disorder with 11.8 million deaths annually.

As such the need is evident. Having said this, mental health conditions are determined by a very complex interplay of individual and social states of stress, as well as personal vulnerabilities. Similarly, the pharmacological implications and targets are multi-variate with a limited number of in vivo models, poor translational outcome in the clinic, and as in the case of addiction, with few pipeline drugs targeting the underlying craving. These confounding factors limit the opportunity for big pharma, especially considering the poor access to the complex small molecule pharmacophores known to have a link to the target disease and from which drug discovery programmes can be rolled out.

RA: Could you discuss the concept of new-to-nature?

MJ: Natural products from plants did not evolve to combat human diseases. In plants they are synthesised to fulfil specific disparate biological functions, including defence against predators, response to environmental change and chemoattraction. Thus, it is maybe not surprising, that natural products are known to elicit adverse effects in humans due to suboptimal ADME properties, tox, efficacy, and physiochemical properties. This was first demonstrated in 1899 with the production of aspirin, a semi-synthetic drug based on the natural product salicin isolated from white bark (Salix alba). Since then, drug discovery in the 20th century has largely focused on the use of synthetic chemistry for hit-to-lead identification using cheap petroleum-derived bulk chemicals to make and screen huge libraries of synthetic small molecules. While the end of last century witnessed a dampener on the rate of synthetic small molecule discoveries that made it into the clinic, natural products and their new-to-nature derivatives sourced from semi-synthesis still make up more than half of all drugs in clinical use around the world.

RA: Biomia integrates halogenation into the design of compounds. What benefits does this bring?

MJ: Biomia is able to regio-selectively and stereo- specifically incorporate halogens into complex plant natural products using a combination of enzyme-based biocatalysis and bioprocess know-how. This allows us to build small molecule libraries not possible to make in nature, and difficult to chemically synthesise due to the multiple chiral centres and reactive side groups often found in plant natural products. The benefits of introducing carbon-halogen bonds in small molecule natural products as drug leads are evident, with more than 40% of the drug leads going into clinical studies being halogenated, and approx. 25% of approved drugs having a halogen incorporated.

This said, the mechanistic underpinnings associated with benefits of introducing halogens into bioactive small molecules are elusive, but several theories exist, including that the ability to form halogen bonds increase hydrophobicity, improve drug–target binding affinity, as well as tuning ADME/T properties.

RA: How much potential do monoterpenoid indole alkaloids (MIAs) have within disease areas?

MJ: MIAs have been used in the clinic for decades for the treatment of human malignancies. While some MIAs are even listed as essential medicines by the WHO, many are acclaimed for their therapeutic potential as part of ethnobotanicals, while others again have been abandoned due to adverse effects or lack of clinical evidence.

This said, MIAs constitute a large subclass of specialised metabolites from plants with >3,000 chemical structures defined by a heterocyclic nitrogen, usually with basic properties, which together with an indole scaffold makes them particularly pharmacologically active. However, despite the high pharmaceutical potential of MIA scaffolds and the documented therapeutic potential of MIA derivatives, they have until now not formed the basis of large-scale drug libraries that can be screened for new or improved bioactivities. This is largely due to the challenges sourcing them by means of poor-yielding extraction from natural resources. Likewise, the chemical complexity that complicates total synthesis of MIAs (and natural products in general) also limits the chemical modifications that can be made with sufficient yield, thereby precluding systematic derivatization of MIA scaffolds for drug library generation.

In medicinal chemistry communities, and in particular in Biomia, we take a biocatalytic approach to tackling this problem. With the acknowledged and clinically proven link between MIA chemistry and target diseases discovery programmes derived from MIAs are considered an excellent departure point for Biomia to build our pipelines.

DDW Volume 25 – Issue 1, Winter 2023/2024

Michael Krogh JensenBiography:

Michael Krogh Jensen is a Co-founder and CEO of Biomia, founded in 2022. He holds a PhD in molecular biology from University of Copenhagen and did postdoctoral training at the Max-Planck Institute (GER) and Stanford University (US), before joining the Technical University of Denmark as a group leader in 2013 with a focus on synthetic biology.

 

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