Ann: AGM Company Presentation, page-22

Thought perhaps that I should add what I see as another possible explanation.

As discussed in a post a couple of weeks ago (ASO, DMD and CPPs – 05/11/18))

Just months prior to eteplirsen’s approval by the FDA, Biomarin was unsuccessful in gaining approval for its ASO exon 51 skipping drug, drisapersen (Kyndrisa). Drisapersen was one of four exon-skipping ASOs (the others targeting 44, 45 and 53) that Biomarin purchased from the Dutch company, Prosensa for up to $840 m in 2014.

The FDA rejected drisapersen due partly to safety concerns, but primarily because clinical trials of the drug had not effectively demonstrated a clear increase in levels of dystrophin. In June 2016, Biomarin announced that it was discontinuing further clinical and regulatory development of drisapersen and its other pipeline ASO drugs.

A year later, following an ongoing patent dispute between Biomarin and Sarepta related to the use of exon-skipping ASOs in the treatment of DMD, Sarepta agreed to pay BioMarin a one-time $35 million payment, plus regulatory and commercial milestone payments and royalties for exons 51, 45, 53, and possibly on future exon-skipping products. Sarepta currently has therapies targeting exons 45 and 53 in Phase 3 development. Under the settlement terms, BioMarin retains rights to convert that license to a co-exclusive right should it decide to proceed with its own exon-skipping therapy for DMD (its ASO therapies targeted exons 51, 45, 53 and 44).

Although exon-skipping ASOs have disappeared from Biomarin’s pipeline on its company website, its scientists, together with researchers from Leiden University, authored a paper (submitted December 2016 and published in Molecular Therapy in January 2018), titled “Cyclic Peptides to Improve Delivery and Exon Skipping Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy”. The authors describe previous mouse model experiments aimed at improving ASO delivery, including use of the TAT-peptide. In seeking an alternative approach the researchers used phage display screening of a cyclic peptide library to identify candidate muscle-homing peptides suitable for conjugation. Peptides for the experiment were sourced from New England Biolabs. The researchers then conjugated the lead peptide to an ASO for their DMD mouse model experiment, achieving a 2-fold increase in delivery and exon skipping in all analyzed skeletal and cardiac muscle. While selected as a muscle-homing peptide, uptake was also increased in the liver and kidney. The compound was observed to be well tolerated. The authors concluded that the identified peptide had the potential to facilitate delivery of AONs (ASOs) and perhaps other compounds to skeletal and cardiac muscle.

Biomarin was revealed as one of a number of “target customers” for Phylogica at last year’s AGM. It will be interesting to see if the therapeutic read outs from Phylogica’s flagship program of CPP ASO conjugates in DMD will spark interest from Biomarin in resurrecting its ASO in DMD program.


If Biomarin (which has been identified as a “target customer” by Phylogica) wants to see a return on the $840 million it paid in 2014 for Prosensa’s four exon-skipping ASOs, it needs to find a way to deliver the ASOs into the required cell tissues with higher efficiency and reduced toxicity. And because Sarepta currently dominates this space, Biomarin's results would need to outperform those of Sarepta’s PPMOs.

In this scenario, PYC could source its PMOs from Biomarin and then measure its results against available data from Sarepta’s PPMO studies (because that is the standard which must be outclassed). Hence all the mentions of Sarepta's PPMO program.

Biomarin’s market cap, by the way, is double that of Sarepta.