2Q21 Global & International Equity

Global Life Sciences Fund

Market Environment • Health care stocks delivered gains during the quarter, benefiting from economic re- openings, clinical advances and attractive valuations. • These trends were especially beneficial for life sciences tools and services firms and biotechnology, which on average outperformed during the quarter. • The only sub-sector to finish the period in negative territory was health care distributors, weighed down by lingering concerns about potential drug pricing reform

FUND in the U.S.

Performance Summary The Fund underperformed its primary benchmark, the MSCI World Health Care IndexSM, as well as secondary benchmark, the S&P 500® Index, for the quarter ended June 30, 2021. Detracting from returns was positioning in biotechnology, particularly small caps, as investors favored equities that could more directly benefit from the economic reopening. Stock selection in pharmaceuticals contributed positively to performance.

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Portfolio Discussion Looking at individual holdings, Olema Pharmaceuticals was the top detractor. Like many small-cap biotechs, Olema experienced a significant rally following its initial public offering at the end of 2020. As such, the stock gave up some gains during the quarter as investors began to take profits. However, the company’s long-term outlook

COMMENTARY has not changed. Olema is developing treatments for cancers that afflict women, including OP-1250, a potential best-in-class therapy for hormone-driven breast cancer (roughly two-thirds of all breast cancers). The company recently started phase 1/2 trials, with initial data expected later this year. Travere Therapeutics also weighed on performance. The biotech is developing sparsentan as a treatment for focal segmental glomerulosclerosis (FSGS), a rare kidney disease. Although sparsentan had delivered positive interim data, in May, the Food and Drug Administration (FDA) questioned the endpoints of the study, hampering prospects for accelerated approval. While the news was disappointing, we believe the high, unmet medical need for FSGS will eventually lead to sparsentan’s approval and launch. In the meantime, sparsentan is being developed for a second indication, IgA nephropathy, for which the clinical trial design has more acceptance. A phase 3 readout is expected in the third quarter. Other holdings contributed positively to performance, including Agilon Health. The company is focused on delivering value-based care for Medicare Advantage, which helps administer health insurance benefits for seniors in the U.S. To do so, Agilon leverages technology to analyze patient data, find efficiencies and tie reimbursement to patient outcomes (rather than fee for service) for a network of independent, primary care physicians. The net result is often better outcomes for both patients and

Page 1 of 3 Global Life Sciences Fund (quarter ended 6/30/21) physicians, while the network offers potential for scalability. including oncology, where sales increased 16% year over year, Agilon completed its initial public offering in April, and on the as well as cardiovascular, renal and metabolism. In our view, first day of trading the stock climbed by more than a third. AstraZeneca has one of the best growth profiles among large- cap global pharma companies, with a diversified product line AstraZeneca was another significant contributor. The company and wide geographic reach. In addition, AstraZeneca is reported quarterly earnings that beat consensus expectations expected to complete its acquisition of despite costs associated with its COVID-19 vaccine. this year, which will be significantly accretive and boost the (AstraZeneca has pledged not to take any profits during the firm’s exposure to the burgeoning rare disease market. pandemic.) Many areas of the firm delivered solid growth,

Top Contributors Average Relative Top Detractors Average Relative Weight (%) Contribution (%) Weight (%) Contribution (%) Johnson & Johnson 1.16 0.43 Olema Pharmaceuticals Inc 0.46 -0.32 Agilon Health Inc 0.39 0.24 Travere Therapeutics Inc 0.43 -0.28 Verve Therapeutics Inc 0.08 0.23 Insmed Inc 1.01 -0.26 AstraZeneca PLC 4.22 0.22 ALX Oncology Holdings Inc 0.51 -0.25 LifeStance Health Group 0.11 0.19 2.25 -0.24

The holdings identified in this table, in compliance with Janus Henderson policy, do not represent all of the securities purchased, held or sold during the period. To obtain a list showing every holding as a percentage of the portfolio at the end of the most recent publicly available disclosure period, contact 800.668.0434 or visit janushenderson.com/info. Relative contribution reflects how the portfolio's holdings impacted return relative to the benchmark. Cash and securities not held in the portfolio are not shown.

Manager Outlook Portfolio Management With Congress focused on passing a bipartisan infrastructure bill, drug pricing reform has taken a backseat in the U.S. political discourse. In addition, in June, the Supreme Court dismissed a case challenging the validity of the Affordable Care Act, the seminal legislation that expanded health care coverage for Americans. For now, these events have helped to alleviate the political overhang Andy Acker, CFA for health care and allowed investors to refocus on the advances being made in drug development and health care delivery. Innovation can lead to volatility and even controversy, as we saw with the recent decision by the FDA to approve Aduhelm for the treatment of Alzheimer’s. The approval came despite doubts about the drug’s efficacy and the potential enormous cost to the Medicare system. We believe the decision is emblematic of how innovation and regulation can get out of sync, especially when progress occurs rapidly. Health care stocks are often subject to binary events, but the sector could experience volatility as medical breakthroughs continue and regulators endeavor to keep up. As such, we think it is ever more important to focus on fundamentals, analyzing the science and commercial opportunity of new products and services. Aduhelm, for one, could now face competition sooner than expected as a result of the low approval standard set by the FDA. In this environment, we believe the best way to capitalize on health care’s significant growth prospects is to take the long view and look for innovation that offers the potential to deliver durable benefits to both patients and investors.

Page 2 of 3 Global Life Sciences Fund (quarter ended 6/30/21)

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Please consider the charges, risks, expenses and investment future. Such results should not be the sole basis for evaluating material facts in making objectives carefully before investing. For a prospectus or, if available, an investment decision. Investing involves risk, including the possible loss of principal and fluctuation of a summary prospectus containing this and other information, please value. call Janus Henderson at 800.668.0434 or download the file from Foreign securities are subject to additional risks including currency fluctuations, janushenderson.com/info. Read it carefully before you invest or political and economic uncertainty, increased volatility, lower liquidity and send money. differing financial and information reporting standards, all of which are magnified in emerging markets. Past performance is no guarantee of future results. Call 800.668.0434 or visit janushenderson.com/performance for current month-end performance. Concentrated investments in a single sector, industry or region will be more susceptible to factors affecting that group and may be more volatile than less Discussion is based on the performance of Class I Shares. concentrated investments or the market as a whole. As of 6/30/21 the top ten portfolio holdings of Janus Henderson Global Life Sciences Initial Public Offerings (IPOs) are highly speculative investments and may be Fund are: AstraZeneca PLC (4.50%), UnitedHealth Group Inc (3.99%), Roche Holding subject to lower liquidity and greater volatility. Special risks associated with IPOs AG (2.91%), AbbVie Inc (2.81%), Merck & Co Inc (2.75%), Novartis AG (ADR) (2.59%), include limited operating history, unseasoned trading, high turnover and non- Humana Inc (2.46%), Boston Scientific Corp (2.46%), (2.29%) and repeatable performance. Thermo Fisher Scientific Inc (2.28%). There are no assurances that any portfolio currently SM holds these securities or other securities mentioned. MSCI World Health Care Index reflects the performance of health care stocks from global developed markets. The opinions are as of 6/30/21, are subject to change and may not reflect the views of ® others in the organization. Janus Henderson may have a business relationship with S&P 500 Index reflects U.S. large-cap equity performance and represents broad U.S. certain entities discussed. The comments should not be construed as a recommendation equity market performance. of individual holdings or market sectors, but as an illustration of broader themes. Index performance does not reflect the expenses of managing a portfolio as an index is For equity portfolios, relative contribution compares the performance of a security in the unmanaged and not available for direct investment. portfolio to the benchmark’s total return, factoring in the difference in weight of that Janus Henderson is a trademark of Janus Henderson Group plc or one of its subsidiaries. security in the benchmark. Returns are calculated using daily returns and previous day © Janus Henderson Group plc. ending weights rolled up by ticker, gross of advisory fees, may exclude certain derivatives Janus Henderson Distributors and will differ from actual performance. High absolute short-term performance is not typical and may not be achieved in the

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