The Lion and the Elephant, page-2

Does antisense platform company, Ionis Pharmaceuticals, provide an aspirational blueprint for PYC?

Ionis Pharmaceuticals is perhaps best known as the developer of the (breathtakingly expensive) antisense drug for SMA, Spinraza (nusinersen). Approved by FDA in December 2016, Spinraza achieved US$1.7bn in revenue in its second year on the market.

Shortly after commencing its first Phase 1 trial in children with SMA in December 2011, Ionis (then Isis) entered into an exclusive, worldwide option and collaboration agreement with Biogen for the two companies to develop and commercialize nusinersen. Ionis received an upfront payment of $29m and was eligible to receive up to $45 m in milestone payments associated with pre-licensing clinical development, for which it was to be responsible. After successful interim Ph2/3 trial results were announced in mid-2016, Biogen exercised its option to license nusinersen for a US$75m license fee, milestone payments up to US$150m, and tiered royalties on sales. Biogen also took over all further development and commercialization costs.

Ionis’ first marketed drug was fomivirsen (Vitravene), an intravitreal therapy which was approved by the FDA in 1998 for the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. Fomivirsen was the first approved antisense drug. Novartis licensed fomivirsen but withdrew it from the market after just a few years as the incidence of CMV dramatically declined with the advent of HAART treatment for HIV/AIDS.

Lean years followed for Ionis, which suffered a series of clinical trial failures caused by both lack of drug efficacy and immune reactions. Its next ASO drug approval wasn’t until 2013 when the FDA approved mipomersen for the treatment of a genetic form of high cholesterol. Like fomivirsen, it wasn’t a commercial success. Weak sales followed poor marketing and failure to gain regulatory approval in Europe.

However, Ionis persisted and 2016 saw both FDA approval for nusinersen in SMA as well as the company’s first year of adjusted operating profitability (which has continued in the two years since).

Ionis now has more than 40 compounds in various stages of development and expects to have at least 10 of them in late-stage trials within the next few years.

It has signed multiple collaborative deals with big pharma such as GSK, Roche, AstraZeneca, Bayer and Novartis. It has also attracted repeat customers. Following the success of Spinraza, Biogen entered into a 10 year collaboration with Ionis in April last year to develop novel antisense drug candidates for a broad range of neurological diseases. Biogen paid Ionis $1 bn in cash, including an equity investment in Ionis stock and an upfront payment.

Ionis has also forged deals with smaller biotechs, such as ProQR. Last year, ProQR paid Ionis a more modest upfront payment of $2.5 million in ordinary shares in exchange for the worldwide rights to IONIS-RHO-2.5Rx, now called QR-1123. This candidate is being developed specifically for autosomal dominant retinitis pigmentosa (adRP) caused by a P23H mutation in the rhodopsin gene. Under the deal, Ionis stands to collect an undisclosed sum in milestone payments, to be made in cash or equity and 20% royalties on net sales.

The name ProQR will be familiar. The Dutch RNA specialist biotech’s early research was referenced in both PYC’s July presentation and 22 August announcement and it was one of a number of competitor companies identified in last month’s presentation. It was also discussed in more detail in a post in August. The different reporting of pre-clinical results by PYC and ProQR makes it difficult to compare, but it is apparent that ProQR’s LCA leading drug candidate, as well as its retinitis pigmentosa candidate in-licensed from Ionis, achieved efficacy at a much higher dose than that which succeeded for PYC in its early experiments.