First, it’s worth revisiting this (June, 2020) PYC slide which shows where PYC sits within the RNA Therapeutics landscape compared with companies mentioned in this post - Alnylam, Dicerna, Ionis and Sarepta.
The Dive Insight section of this article explains the connections between RNAi oligonucleotide company, Alnylam Pharmaceuticals, and Novartis. The two companies first partnered in 2005 but Novartis cut ties five years later. As the RNAi sector struggled to solve delivery challenges, early pharma interest waned. Anylam had to sack a third of its workforce but pushed ahead with its development work.
The head of R & D at Alnylam nominated the delivery of its drugs to the relevant target organ as the company’s biggest single challenge. Alnylam subsequently solved this challenge through development of a GalNAc conjugate platform and by licensing in a lipid nanoparticle (LNP) delivery platform from Arbutus.
The many years of struggle paid off in 2018 when Alnylam won approval for the first RNAi drug, Onpattro. Since then, it has won three more approvals, the most recent FDA approval being just two weeks ago for Leqvio for high cholesterol (as referred to by Linsanity).
Alnylam’s progress has been reflected in its market capitalization. Ten years ago, prior to solving the challenge of drug delivery, Alnylam’s market cap was US$300m. The market cap rose to US$3bn five years ago as its leading asset reached late stage, US$14.5bn in early 2018 after its first drug was approved, and US$25bn last year (MC is currently US$18bn).
The approval of Onpattro, which proved that the promise of RNAi could be translated into a commercially successful drug, woke up the sector. In the words of the Alnylam’s CEO “RNAi has got its sexy back”.
Over the following year, Novartis, J & J, Eli Lilly, Regeneron, Roche and Novo Nordisk all struck deals to gain access to RNAi drugs, with Arrowhead and Dicerna benefiting along with Alnylam.
Dicerna was acquired last month by Novo Nordisk for US$3bn+, despite not yet having an approved drug and reporting rather disappointing results in its lead program last year. In the words of one analyst, the Dicerna acquisition "reiterates pharma's appetite for platform technologies that are de-risked and close to commercial stage" and "will have a positive read through to the broader RNAi space."
To date, the key developers of approved antisense oligonucleotides are Ionis (ASOs) and Sarepta (PMOs).
Ionis now has a huge pipeline of ASO drugs, many of which are licensed to pharma such as Biogen, Novartis, Astra Zeneca, Pfizer, Roche GSK and Bayer. Three drugs are approved. The first and best known is Spinraza, which Ionis licensed to Biogen. But Spinraza, as mentioned in an earlier post, now faces competition from two competitor therapies. A second drug, Tegsedi, was approved by the FDA, but with a black box warning. The third,Waylira, has been approved in the EU but the FDA refused to approve it on safety grounds. Tominersen, a Roche-licensed late-stage asset targeting Huntington’s disease was abandoned in May last year after a Phase 3 trial in which deaths were greater in the tominersen group than in placebo.
So, while Ionis has a huge pipeline and multiple partnerships with big pharma, its setbacks (principally related to drug safety) have seen its market cap drop over the past 5 years from US$5.9bn to US$4.3bn.
Meanwhile, Sarepta has developed a more modest pipeline of 14 PMO (and PPMO) drugs, 3 of which are FDA approved. All fourteen (orphan) drugs target subtypes of DMD. Sarepta’s three marketing approvals have been controversial because of perceived minimal levels of clinical efficacy.
In early 2016, prior to approval of its first drug, Sarepta’s market cap was US$550m. Post-approval in September 2016, the market cap rose briefly to US$2.8bn. As revenues began to flow in and a second drug was approved the market cap rose as high as US$13.7bn in late 2020. It is currently US$7.3bn. Sarepta has in recent years chosen to pivot its pipeline towards gene therapies, perhaps in a quest for greater efficacy.
Now, returning to your original question
So why all the interest in all these companies that you keep finding for us….. but nothing for PYC, which keeps telling us is best in class. Just too early...?
As you point out, it’s still early days for PYC, reflected in the company's ~US$300m market cap. I expect modest increase in interest once the CNS lead candidate is announced but more strongly once clinical data starts coming in – provided the data is strong.
PYC will need to demonstrate that its cell-penetrating peptide platform technology can deliver PMO drugs, into multiple organs, much more effectively than Sarepta and more safely and effectively than Ionis’ ASOs. It will also need to prove that its approach offers benefits over the RNAi approach taken by companies such as Alnylam.
As I said, preclinical in CNS is certainly a good start.
PYC has demonstrated PMO delivery and antisense effect at dosages significantly lower than those reported for delivery of both ASO and other RNA therapeutics, and using research-grade material that may under-represent the true efficacy of PYC’s PPMOs ...
….the PPMO demonstrated a dose dependant response across the target areas of the brain including both the motor cortex (focus in ALS) and the midbrain. Further, there was no evidence of efficacy for the ASO or naked PMO at any dose tested in this model.
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