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#apaperaday: Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein

Today’s pick is from Journal of Clinical Pharmacology by Lee et al on pharmacology for DNA and RNA targeting drugs. DOI: 10.1002/jcph.2172.

The focus of the paper is on rare diseases, which affect less than 1 in 2000 for each rare disease, but combined affect as much as 8% of the population because there are so many rare diseases. 80% of rare diseases is genetic, often involving a single gene.

Thus, therapies targeting a gene or gene transcripts or adding a gene are potentially therapeutic for these diseases. Authors give many examples, including SMA, for which there is a gene addition therapy (zolgensma), a gene transcript targeting therapy (spinraza) anda chemical drug that affects splicing (risdiplam/evrysdi) available now. Authors outline the challenges of rare disease therapy development: often numbers are small in clinical trials, which makes optimizing the dose based on pharmacological findings challenging.

Modelling for PK/PD and also physiologically based pharmacokinetic (PBPK) modelling can help bridge the gaps. In the paper they use examples from trials and approved drugs. I do not know how the examples were selected. For some it makes sense, but for some it does not.

e.g. they include patisiran under siRNAs but do not include any of the other approved siRNA drugs – while the galnac conjugate is an important addition/thing to consider also from a pharmacological perspective. Galnac is however not discussed.

For single stranded ASOs inotersen is discussed – again a missed opportunity to discuss galnac conjugations and compare the changed PK/PD properties. Anyway: for the things discussed, authors discuss first genome editing, where most of the pharmacology is due to delivery tools.

Delivery of mRNA expressing cas9 with lipid nanoparticles works for the liver, while for other organs and cells (ex vivo editing) viral vectors are needed. Challenges are potential off target editing and from a pharmacological perspective finding the right dose.

For transcript targeting patisiran and inotersen + nusinersen are discussed. For patisiran PK/PD modelling helped to find the correct dose of 0.3 mg/kg per 3 weeks, while for nusinersen it helped to set a fixed dose (12 mg) rather than one corrected for weight.

Authors also discuss milasen, the first N=1 ASO developed by Tim Yu for a patient with Batten disease. indicating it is FDA approved – this is not correct. FDA accepted the IND, so it is approved to use in a clinical setting, but the drug is not approved for marketing.

Authors discuss the different PK/PD properties of the ASOs when delivered systemically and when delivered intrathecally. Even for the latter, different doses are used when motorneurons are targeted (nusinersen, 12 mg) or when the brain is targeted (milasen 42 mg).

Authors also discuss chemical drugs and proteins and outline the immunogenicity of the proteins. However, we know that some ASOs can also trigger an immune response and cas9 is immunogenic and when delivered with a viral vector, that will also be immunogenic.

Authors end by outlining how the regulators are involved in providing guidance for using oligonucleotide drugs and optimizing pharmacological modelling for rare diseases. Indeed regulators are very open to having a dialogue (personal experience).

I am not sure what to think of the paper. I like the different perspective that is generally not provided. However, the title suggests a focus on DNA and RNA targeting, but other drugs are also included. Furthermore, authors made a selection without elaborating how/why.

Also they missed some important aspects (e.g. Galnac)…I would not recommend this paper I’m sorry to say. There are some interesting observations and statements, but also missed opportunities.