Central nervous system (CNS) disorders like multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, epilepsy, as well as psychiatric disorders have treatment options, but many have to cross the blood-brain barrier and in doing so can lose potency.
With therapeutics for CNS disorders being both small molecules and biologics, vehicles to deliver the drug to the CNS is the biggest challenge. However, innovations like intranasal administration and viral vector systems are being put to work.
To uncover some of the challenges and innovations occurring in CNS, BioPharma-Reporter (BPR) spoke with Raj Mehra (RM), CEO of Seelos Therapeutics, a clinical-stage biopharmaceutical company focused on therapeutics for such disorders.
BPR: What are some of the challenges for drug delivery in CNS, and what innovations are being developed to address them?
RM: Some of the biological approaches have been proven to be ineffective, not because of efficacy but because the drug delivery systems are not able to get enough of the drugs across the blood-brain barrier.
An approach that has been advanced is the vector system, that’s one way to get delivery where you want it [to the CNS]. However, it has some side effects – issues that need to get flushed out in the next few years.
The other approach that looks very promising, and few have explored until now, is getting the drugs administered intranasally.
Whether the drug is in a liquid formulation or solid, you can practically put those [formulations] in a device that can [be administered in an] intranasal spray.
What we’ve seen is that it is one of the quickest and fastest ways to get the drug into the CNS by bypassing the gastrointestinal effect, and a smaller dose can provide a much better efficacy. Fast-acting drugs delivered intranasally are going to be a big trend.
BPR: Why have intranasal delivery formulations and systems become a recent trend?
RM: People did not think about it, people thought that if a drug is not orally available, “How about coming up with a subcutaneous delivery or come out with a patch?” The patches had mixed records, but subcutaneous delivery has a decent record.
When people tried to address the CNS space, they realized its limitations. If you were to do an antibody approach [to address the CNS then] you’d need a large amount of dosing to assume that .1% will eventually cross the blood-brain barrier. So, that approach limitation is what made people start thinking: “Can we pursue other approaches in the intranasal formulation?”, and people saw remarkable efficacy.
One of the approaches to address aggregates in the CNS disease is an antibody approach – which are large biologicals.
The issue was when you have an antibody approach, they have created antibodies that are very specific disease aggregates, only leaving the monomers alone which are needed for the body, and contains and reduces these aggregates (i.e. you can have a disease-modifying potential for a disease like Parkinson’s).
That [disease modifying potential] we have been waiting and hoping for forever. The issue that we saw there is that antibodies do not cross the blood-brain barrier easily; so if you were to come up with a 20g dose, you hope to get 20mg into the CNS.
So, that’s one approach and the other approach is a small molecule approach. We are going to pursue a small molecule approach where you don’t need the high dose, and the delivery mechanism could be either intranasal or it could be a vector approach -- but these things need to be worked upon.
But that’s what we are looking forward to because up until now all the therapies available for Parkinson’s were just treating the symptoms – none of them were stopping the disease or halting the progression. Now we understand it but the challenge [remains] the delivery mechanism.
BPR: How has manufacturing of this new type of drug delivery for CNS changed as the formulations have changed?
RM: It’s becoming more like a drug and device – you don’t just have a pill that you deliver orally, you have a drug that needs to be formulated for a device.
On the formulation side, it always comes back to the same old issue: if your drug is small molecule than it’s relatively easy to fit into the transporters because your drug is either water-soluble, or it is not soluble but you can come up with nanoparticles and new technologies that can make it palatable for it to be transported to the CNS.
However, the biologics will have some challenges. These transporter systems [needed for the CNS innovations], generally speaking, have a limitation as you can’t have a big biologic easily available to be transported.
So, the challenge will be most of the work that should be done on the CNS side for formulation -- coming up with a relatively small footprint of the drug that can be easily put into the vehicle.
You will have those inherent limitations until down the road, perhaps, we can overcome that. So, the formulations have to be relatively small footprint therapies.
BPR: Do you have any other thoughts on how the industry has been innovating in CNS?
RM: I think we need to urge our large pharma companies to step up to the plate and not just remain focused on oncology because the CNS diseases are becoming much more prevalent and as deadly.
Raj Mehra, a former biotechnology money manager for 30 years left that role to start a company. He leads NYC-based Seelos Therapeutics as founder and CEO, the startup biotech company. After a recent merger with Apricus Biosciences, Inc. Mehra serves as chairman and CEO of the merged company.