whyframestudio/iStock via Getty Images I have been a follower and a fan of Ionis (NASDAQ:IONS) since 04/2018’s Ionis article “Ionis: Cash, Catalysts And More”. In 03/2022’s “Ionis: At A Show-Me Crossroads” (“Crossroads”), I reflected on why Ionis had fallen back from its glory days when it had showed promise of trading up to $100 and discussed its then forward prospects . In this article, I update Crossroads based on latest available Ionis developments, including its Q3,2022 Earnings call (the “Call”) and CEO Monia’s presentation at the 01/2023 41st Annual J.P. Morgan Healthcare Conference (the “Presentation”). Ionis’ ALS SOD1 PDUFA is fast approaching. Ionis has long generated healthy royalty revenues from its SPINRAZA (nusinersen) deal with Biogen (BIIB). They totaled ~$268 million in 2021 compared to ~$287 million in 2020. Its Q3, 2022 10-Q reported its product revenues from Spinraza, and lesser revenues from WAYLIVRA and TEGSEDI as set out below: seekingalpha.com This off kilter tri-legged stool of product revenues, with SPINRAZA as the workhorse and TEGSEDI and WAYLIVRA as the distant also-rans, has been the case for several years. As described in Crossroads, Ionis has recently been on something of a losing streak with late stage candidates. Examples include its: Vupanorsen (PF-07285557), that was being evaluated for potential indications in cardiovascular [CV] risk reduction in development with Pfizer’s (PFE); Tominersen (HTT) (RG6042, IONIS-HTTRx) that was being evaluated by Roche in treatment of Huntington’s Disease [HD]. In 10/2021 Ionis’ tofersen failed to hit the primary endpoint in its phase III trial in treatment of superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis. It looked as if it were going to count as a third failure. However Biogen parsed the data and found favorable trends in secondary and exploratory markers. Accordingly it went ahead and filed an NDA. In 07/2022 Ionis announced that the FDA accepted Biogen’s NDA for tofersen in treatment of SOD1-ALS. The FDA granted the application priority review with a PDUFA date of 01/25/2023. Tofersen is currently under submission to the FDA with a PDUFA of 04/25/2023, extended three months from 01/25/2023. If tofersen is approved it will be a feather in Ionis’ cap and boost to its credibility. ALS is not a common disease; only a small percentage of ALS patients have the SODI variation. Accordingly, tofersen may not provide too much of a financial boost even if approved. Ionis’ deal with Biogen was entered into in 2013 and calls for unspecified milestones and “tiered royalties up to the midteens”. Ionis has more appealing opportunities over the next few years. Knowledgeable Ionis bulls are looking beyond the SOD1 PDUFA to Ionis’ next three opportunities teed up in its bullpen. These are each ligand-conjugated (LICA) investigational antisense molecules. They include: Eplontersen, a medicine designed to reduce the production of transthyretin (TTR protein), to treat all types of TTR amyloidosis (ATTR), a systemic, progressive and fatal disease.; Olezarsen to treat cardiometabolic disease and acute pancreatitis due to elevated triglyceride levels; and Donidalorsen designed to reduce the production of prekallikrein, which plays a key role in the activation of inflammatory mediators associated with acute attacks of hereditary angioedema [HAE] . Of these three, eplontersen is the kingpin in terms of potential in terms of both market size and imminency. Its key attributes are set out in its panel below from Presentation slide 6. ir.ionispharna.com Importantly and not mentioned on the slide is the Ionis’ 12/2021 eplontersen collaboration with AstraZeneca (AZN). the financial arrangements on the deal are richer than the earlier SOD1 deal. They include: …upfront payment of $200m and additional conditional payments of up to $485m following regulatory approvals. It will also pay up to $2.9bn of sales-related milestones based on sales thresholds between $500m and $6bn, plus royalties in the range of low double-digit to mid-twenties percentage depending on the region. The collaboration includes territory-specific development, commercial and medical affairs cost-sharing provisions. The deal looks and sounds sweet as shown by the Presentation; I have a nagging eplontersen concern; if approved it could be a low priority for AstraZeneca. Its 09/2022 Rare Disease Investor Presentation has several Amyloidosis focused slides; none of them mention eplontersen. There is always a risk that nice royalty deals backfire when the licensee prefers to spend promotion dollars on its own wholly owned therapies. From a licensee’s perspective a royalty is a tax. We all know how taxpayers hate taxes and go to great lengths to avoid them. Olezarsen is currently wholly owned by Ionis. Its key attributes from its Presentation slide 6 panel include potential blockbuster sales, however its first pivotal readout will be for treatment of familial chylomicronemia syndrome [FCS]. Unfortunately FCS is a rare disease with ~1,500 US patients it is still waiting on data from its first pivotal trial expected in mid-2023. Olezarsen’s larger indication, severe hypertriglyceridemia TG >500 mg/dL [SHTG], is being investigated in several trials. During the Call EVP & CDO Geary reported: CORE, our pivotal — our first pivotal study in patients with SHTG remains on track for data CORE 2, our confirmatory pivotal study in the same population is now underway with data also expected in 2024. We recently initiated ESSENCE a supportive Phase III study. ESSENCE is designed to build out the safety database for the much larger SHTG indication. With first-mover advantage, we remain very confident in the potential of olezarsen to be a substantial driver of future growth. I read this as indicating that Olezarsen is unlikely to be a big revenue driver until 2025 or beyond. As for its third and last upcoming pivotal readout for donidalorsen, its Presentation slide 18 shows that it offers tremendous, albeit less than blockbuster, revenue potential. ir.ionisharma.com During the Call Geary reported that he also expected a key data readout from it in 2024. The Ionis story is undergoing a lengthy gestation; its finances are solid but a long way from profitable Ionis, founded in 1989, has tantalized its shareholders with its oversized potential over the years. Frustratingly it has yet to achieve profitability. It has proven to be an entirely different breed of cat from the run of a mill developing biotech. Its “Liquidity and Capital Resources” (p. 39) from its Q3, 2022 10-Q makes for fascinating reading: We have financed our operations primarily from research and development collaborative agreements. We also finance our operations from commercial revenue from SPINRAZA royalties and TEGSEDI and WAYLIVRA commercial revenue. From our inception through September 30, 2022, we have earned approximately $6.3 billion in revenue. We have also financed our operations through the sale of our equity securities and the issuance of long-term debt. From the time we were founded through September 30, 2022, we have raised net proceeds of approximately $2.0 billion from the sale of our equity securities. Additionally, from our inception through September 30, 2022, we have borrowed approximately $2.1 billion under long-term debt arrangements to finance a portion of our operations. That is a ratio few fledgling biotechs can match — revenues of $6.3 billion, financings aggregating $4.1. The very title to Ionis’ Presentation slide 25 below provides a reassuring capstone to the Ionis story: ir.ionispharma.com Conclusion I have rated Ionis as a hold even though I am quite bullish about its long-term prospects. It has catalysts aplenty, including those I have discussed and others discussed in the Call, as for example: imminent Phase 3 trial initiations for: Bepirovirsen, a potentially transformative treatment for people living with chronic hepatitis B: IONIS-FB-LRx which met its primary end point demonstrating substantial and clinically meaningful reductions in 24-hour urinary protein in patients with IgA nephropathy with a mean reduction of 44%. I don’t rate Ionis a buy only because it carries a market cap (01/12/2023) of $5.39 billion. It is primed for disappointment following a decision on its SOD1 PDUFA. If the ruling is positive, it will only provide modest revenue. If it is negative, it will cast doubt on its entire pipeline.