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Ionis Pharmaceuticals, Inc. (IONS) - Wall Street’s Best Digest Daily Alert - 12/16/20

This biopharma is forecasted to grow at an annual rate of 98% over the next five years.

This biopharma is forecasted to grow at an annual rate of 98% over the next five years.

Ionis Pharmaceuticals, Inc. (IONS)
From The Medical Technology Stock Letter

IONS and its partner AstraZeneca initiated a Phase IIb trial of ION449 (AZD8233), which was designed to reduce blood cholesterol levels in patients with dyslipidemia by targeting PCSK9, an important and proven regulator of low-density lipoprotein cholesterol (LDL-C). The Phase IIb, randomized, double-blind, placebo-controlled trial will enroll approximately 108 participants, aged 18-75, who have LDL-C levels between 70 and 190 mg/dL and are receiving moderate- or high-intensity statin therapy. The primary objective is to assess the effect of different doses of ION449 on LDL-C compared to placebo at Week 12 in patients taking baseline statin therapy. The study will evaluate three dose levels of ION449 versus placebo, all administered once-a-month by subcutaneous injection. Safety and tolerability will be evaluated along with a number of secondary endpoints (

In a Phase I trial recently reported at the AHA (11/13-17), single subcutaneous doses of ION449 (AZD8233) demonstrated dose-dependent mean reductions in circulating plasma PCSK9 and LDL-C levels of >90% and up to 70%, respectively, in subjects who had a baseline LDL-C between 100 and 190 mg/dL without concomitant statin therapy.1 Doses up to 120 mg were evaluated. ION449 was observed to be safe and well-tolerated at all dose levels. In our view, despite the heavy competition in the PCSK9 space, ‘449 has the potential to be a best-in-class molecule given the 70-90% reductions seen to date. As a reminder late last year Novartis paid $10 billion to acquire MTSL Rec MDCO for its antisense PCSK-9 compound, Inclisiran – The Medicine Company’s only product.

IONS partner Pfizer also announced the initiation of the Phase III BALANCE study for AKCEA-APOCIII-LRx in adult patients with familial chylomicronemia syndrome (FCS). FCS is a debilitating genetic disease characterized by severely high plasma levels of triglycerides and a risk of unpredictable and potentially fatal acute pancreatitis. In addition to acute pancreatitis, FCS patients are at risk of chronic complications due to permanent organ damage, including chronic pancreatitis and pancreatogenic diabetes. The Phase III BALANCE study is a global, multi-center, randomized, double-blind, placebo-controlled study enrolling up to 60 patients (age 18 and over) with FCS. Participants will be randomized in a 2:1 ratio to receive AKCEA-APOCIII-LRx or placebo via subcutaneous injection once every four weeks for a total 53-week treatment period. In addition to FCS, Ionis is evaluating additional indications for AKCEA-APOCIII-LRx development. (

IONS and AstraZeneca are also partners on ION455, for nonalcoholic steatohepatitis (NASH). ION455 is the second medicine for the treatment of NASH that Ionis has partnered with AstraZeneca. The companies have also partnered on ION839 (AZD2693), which is designed to inhibit the production of patatin-like phospholipase domain-containing 3 (PNPLA3) protein, a major genetic determinant of NASH progression. Separately, Ionis is also developing a wholly owned NASH program. ION224 is designed to reduce the production of DGAT2, or diacylglycerol acyltransferase 2, for treating patients with NASH.

All three of these drug development candidates were designed using the Ligand Conjugated Antisense (LICA) technology platform which allows for significantly less drug to be used allowing for more convenient dosing and less potential side effects. In our view, despite the heavy competition in the PCSK9 space, ‘449 has the potential to be a best in class molecule given the 70-90% reductions seen to date. The company has conducted significant research and once a month sub-q dosing will be highly competitive with less frequent dosing. AZ and IONS are also following up with an oral version of ‘449 which also incorporates LICA technology and reported encouraging Phase I data recently at AHA. AZ is clearly voting with its feet and IONS in cardiovascular as the company recently sold its Crestor rights to focus on up and coming innovative new medicines like ‘449.

While the majority of biotech investor focus is on COVID vaccines of late, IONS continues to build its R&D war chest of antisense compounds (>50), many of which may become the next Spinraza (2020 sales >$2 billion). In this environment, any of IONS’ large pharma partnerships (e.g., AZN, Roche, BIIB, PFE, etc.) may turn into an outright acquisition. With cash of $2.3 billion, IONS $7 billion market cap looks attractive to us (especially compared with ALNY’s $15 billion MC).

IONS is a BUY under 75 with a TARGET PRICE of 90

John McCamant, The Medical Technology Stock Letter,, December 3, 2020