Goldman Sachs Decodes AZN/IONS Wainua Phase 3 Trial: New Signals in Cardiology Renaissance

Overview

This report by Goldman Sachs focuses on the Phase 3 clinical trial CARDIO-TTRansform, evaluating the antisense oligonucleotide drug Wainua developed through a collaboration between AstraZeneca and Ionis Pharmaceuticals for treating transthyretin amyloid cardiomyopathy (ATTR-CM). The report details the trial design, baseline characteristics, and comparisons with competing trials such as Alnylam's HELIOS-B. Goldman Sachs posits that while the high rate of combination therapy may reduce event rates and increase the difficulty of achieving statistical significance, the large trial scale and rigorous design are expected to provide robust data sets in the second half of 2026, further supporting the clinical application and market penetration of gene silencing therapies in cardiology.

Core views

Trial Design and Scale Advantages: CARDIO-TTRansform is the largest fully enrolled ATTR-CM trial to date, encompassing 1,432 patients. The trial employs a double-blind design lasting 140 weeks, followed by a 20-week post-treatment assessment period. Patients were stratified and randomized based on New York Heart Association (NYHA) functional class, TTR variant status, 6-minute walk test distance, and concurrent use of TTR stabilizers. Notably, the trial allows enrollment of elderly patients up to 90 years old without an upper limit on NT-proBNP, covering a broader spectrum of disease severity. Challenges and Opportunities in Combination Therapy Context: Compared to Alnylam's HELIOS-B trial, the proportion of patients concurrently using TTR stabilizers (such as Pfizer's tafamidis) was significantly higher in CARDIO-TTRansform (57% vs. 40%), as was the use of SGLT2 inhibitors (18% vs. 3%). Goldman Sachs notes that Key Opinion Leaders (KOLs) show strong interest in the 'stabilizer + silencer' combination therapy. However, the higher rate of combination therapy may lower overall event rates, thereby raising the threshold for achieving statistical significance. Investors are particularly focused on whether Wainua demonstrates additional statistically significant benefit in the subgroup already using tafamidis, which corresponds to the fifth level of secondary endpoint testing. Endpoints and Statistical Power: The primary endpoint is a composite of cardiovascular death and recurrent cardiovascular clinical events (including hospitalization for heart failure exacerbation, myocardial infarction, stroke, etc.) through week 140. Statistical calculations assume a cardiovascular mortality rate of 8.7% in the placebo group; a sample size of n=1,400 provides approximately 85% statistical power to detect a 20% reduction in the primary composite endpoint for the Wainua treatment group compared to placebo (significance level 0.05). Secondary endpoints are ranked by formal testing hierarchy, including changes in 6-minute walk distance, quality of life scores, recurrent cardiovascular events, and all-cause mortality. Valuation and Ratings: For Ionis Pharmaceuticals (IONS), Goldman Sachs maintains a 'Neutral' rating with a 12-month target price of $74, based on DCF analysis (WACC 13%, terminal growth rate 3%). For AstraZeneca, the firm maintains a 'Buy' rating with a 12-month target price of 16,525 pence/$219. Valuation utilizes a hybrid method equally weighting DCF and P/E multiples, suggesting its 2027 expected EPS should trade at a 20x P/E multiple.

Analysis framework

Goldman Sachs employed a detailed clinical trial comparative analysis approach. First, by horizontally comparing CARDIO-TTRansform with other key industry trials (such as HELIOS-B, ATTRibute-CM, ATTR-ACT) regarding inclusion criteria, patient baseline characteristics (e.g., age, NYHA class, NT-proBNP levels), and concomitant medication rates, the potential bias and external validity of trial results were assessed. Second, the statistical design of the trial was deeply analyzed, including the composition of primary endpoints, stratification factors, statistical models (semi-parametric proportional hazards model), and power calculations, to judge the likelihood of trial success and the complexity of data interpretation. Finally, incorporating feedback from KOL interviews, expected clinical data was translated into judgments regarding market dynamics (particularly competition landscape before tafamidis patent expiration in 2031) and company valuations.

Methodology notes

• Company Fundamentals and Financial FrameworkDCF Cash Flow Discounting

  DCF Cash Flow Discounting

  The research report values companies using a discounted cash flow model, projecting future free cash flows and discounting them to present value, combined with weighted average cost of capital (WACC) and terminal growth rate to derive intrinsic value. This is a common method for assessing the pipeline value of biopharmaceutical companies.

• Valuation methodsPE/PEG valuation

  PE/PEG Valuation

  The report references valuation using the Price-to-Earnings (P/E) multiple method for AstraZeneca, combining it with 2027 expected EPS and weighting it against DCF results to provide a more comprehensive relative market valuation perspective.

• Industry/Sector Analysis Framework

  Clinical Trial Design and Statistical Power Analysis

  The report deeply analyzes clinical trial inclusion criteria, endpoint settings, and statistical power. This is a core industry analysis method for assessing the success probability and data quality of biomedical R&D pipelines, directly impacting market expectations for drug commercial potential.

Asset mapping & comparison

Structured mapping from thesis to named assets (strengths, weaknesses, peers, risks).

• AstraZeneca (AZN)

  Beneficiary; Co-developer and primary commercialization driver of Wainua

  Strengths

  Strong cardiovascular commercialization capabilities; Wainua has the potential to be a blockbuster product

  Weaknesses

  -

  Comparison

  Possesses a more mature global sales network compared to pure biotechnology companies

  Risks

  Clinical trial failure, commercial execution risk, pricing pressure, competitive developments, patent exposure

• IONIS PHARMACEUTICALS INC (IONS)

  Beneficiary; Technology provider and co-developer of Wainua

  Strengths

  Leading antisense oligonucleotide technology platform; rich pipeline

  Weaknesses

  Currently not profitable; relies on partners for commercialization

  Comparison

  Technology platform is extensible, but commercial monetization depends on licensing partnerships

  Risks

  Regulatory and reimbursement approval failure, clinical and commercial setbacks, faster competitor progress, safety issues, intellectual property risks

Key data

• CARDIO-TTRansform Trial Enrollment Number1,432 patientsLargest fully enrolled ATTR-CM trial to date
• Concurrent TTR Stabilizer Usage Rate57% (819 patients)Significantly higher than HELIOS-B trial's 40%
• Concurrent SGLT2 Inhibitor Usage Rate18%Significantly higher than HELIOS-B trial's 3%
• Primary Endpoint Statistical Power~85%Assuming 20% reduction in primary composite endpoint and 8.7% CV mortality in placebo group
• IONS Target Price$74Based on DCF analysis, Neutral rating
• AstraZeneca Target Price16,525p / $219Based on hybrid DCF and P/E valuation, Buy rating

Impact & implications

Goldman Sachs believes the results of the CARDIO-TTRansform trial will provide important data support for the ATTR-CM treatment field, particularly regarding 'stabilizer + silencer' combination therapy. If successful, it will reinforce the market position of Wainua and similar gene silencing drugs, establishing combination therapy as the clinical standard before Pfizer's tafamidis patent expires in 2031. This is a major tailwind for AstraZeneca's cardiovascular product pipeline and provides critical validation for Ionis Pharmaceuticals' pipeline value. Despite the challenge posed by the high combination therapy rate to achieving statistical significance, the large sample size and robust design lead Goldman Sachs to maintain a constructive view on the probability of trial success.

Risks

• Clinical trial failure or failure to meet primary/secondary endpoints
• Failure to obtain regulatory approval or reimbursement eligibility
• Ineffective commercialization execution or sales below expectations
• Competitor assets advancing faster or delivering superior data
• New safety events affecting penetration rates
• Intellectual property protection failure and risk of generic entry
• Financial risks due to IONS currently being unprofitable

What to watch

• Data readout from CARDIO-TTRansform trial in the second half of 2026
• Statistical significance of Wainua efficacy within the tafamidis cohort
• Evolution of Key Opinion Leader attitudes towards combination therapy
• Regulatory authorities' stance on approving combination therapy data