As you stated, PYC did announce in 2017 that it had been granted a further US patent (US 2014/0141452 A1) covering the identification of peptides with the ability to enter specific endothelial cells in the brain.
In the “PPMO Superior Delivery to the Brain” mouse model results reported in April 2021, intracerebroventricular (through the skull) injection was used. The Company said that these results supported further study of PPMO technology across multiple neurodegenerative diseases.
However, in the slide presentation of preclinical data which was provided for partnering discussions at the BIO International Convention last year (6/6/23), two different chemistries were proposed for development of an antisense drug therapy for the rare neurodevelopmental disorder, Phelan McDermid syndrome (PMS). One was 2’MOE (naked antisense) and the other PPMO (PYC’s PMO + cell- penetrating peptide drug conjugate). Both modalities were tested in rat brains using intrathecal delivery (lumbar puncture), which bypasses the Blood Brain Barrier.
Finally, the test results presented by PYC last week after this year's BIO International Convention demonstrated restoration of the deficient protein (Shank 3) that causes PMS using PMS patient-derived brain cells (neurons). The announcement stated that the Company was able to generate the positive data with the two different chemistries of RNA therapy it had been working with. It didn’t say which chemistry it had decided to run with, just “This gives us clear line of sight into first in human studies….”
The reason given by PYC for conducting to this stage parallel preclinical development of two different modalities is that PYC’s PPMO approach is not yet recognised as clinically proven and, as such, there is no established pathway.
With respect to the other modality, there have already been 2’MOE oligo drugs approved by the FDA, so there is an established path through preclinical animal studies to clinical validation and commercial success. Given a choice of modality, there is a good chance that a potential partner might opt for what would be considered the lower risk.
To date, there have only been two antisense oligonucleotide drugs approved by the FDA for CNS indications (both neuromuscular).
The first FDA approved CNS ASO was Nusinersen (Spinraza), an Ionis ASO candidate licensed by Biogen, for treatment of spinal muscular atrophy (SMA). It was approved in late 2016. Nusinersen was developed using 2’MOE chemistry. It requires intrathecal administration 3 x per year after initial, more frequent loading doses.
Spinraza’s list price at launch was US $750,000 for the first year and US$375,000 thereafter. Peak sales of US$2.1 bn already occurred in 2019 (third year of sales).
The other FDA approved antisense drug in a CNS indication was Tofersen (Qalsody), also developed by Ionis and licensed by Biogen. It treats amyotrophic lateral sclerosis caused by SOD1 gene mutation (SOD1ALS).
It was approved by the FDA in April 2023 using accelerated approval after it missed primary endpoint in its pivotal trial. Approval is conditional on a further trial that confirms safety and efficacy.
Tofersen was also developed using 2’MOE chemistry. It requires intrathecal administration and needs to be dosed monthly after more frequent initial loading doses.
While there are only 330 people in US estimated to be living with SOD1ALS, Biogen priced the drug relatively low, at ~US$200,000 p.a., perhaps because of competitive treatments, unattractive dosing regimen and unconfirmed efficacy.
Q1 2024 sales of this drug were just US$4.6m and analyst expectations of peak sales is ~US$130m.
There are currently no FDA approved antisense therapies for any neurodevelopmental disorders. Possibly the furthest advanced asset is GTX-102 (seemingly also based on 2’MOE chemistry), developed by GeneTx and since purchased by Ultragenyx. It is due soon to enter a pivotal trial in Angelman syndrome.
Ultragenyx reported Phase 1/2 data that demonstrated “rapid, multi-domain improvements that continued throughout maintenance dosing.” However, the trial was halted at one stage due to high dose patients developing leg weakness.The frequency of dosing for this treatment is unclear and administration is through intrathecal injection.
Ionis is also developing a 2’ MOE antisense drug candidate (ION582) for the treatment of Angelman syndrome and last month reported positive Phase 1/2 data. It is also an intrathecal injection. Intended dosing frequency is unknown.
Which PMS candidate will be progressed and by whom? My current thinking is that this asset might be licensed and developed by someone other than PYC and that the 2’MOE chemistry might be chosen, together with an intrathecal route of administration.
PYC Price at posting:
11.0¢ Sentiment: Hold Disclosure: Held
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