Executive Summary / Key Takeaways

• Achieve Life Sciences is on the cusp of a transformative moment, preparing to submit its New Drug Application (NDA) for cytisinicline for smoking cessation in June 2025, targeting a massive and underserved global market for nicotine dependence treatment.
• Cytisinicline, a plant-based alkaloid, is differentiated by its demonstrated efficacy and a well-tolerated safety profile in clinical trials, offering a potential best-in-class option compared to existing treatments like varenicline and NRTs.
• The company has successfully completed key clinical milestones, including two Phase 3 smoking cessation trials and the required long-term safety exposure study (ORCA-OL), fulfilling critical FDA requirements for the upcoming NDA submission.
• Achieve is strategically preparing for a potential commercial launch in 2026 with an innovative digital-first approach, while also advancing development for a first-in-class vaping cessation indication, bolstered by FDA Breakthrough Therapy designation.
• Despite significant clinical and regulatory progress, the company faces substantial financial risk, including recurring losses and the need for significant additional capital to fund ongoing development and commercialization efforts, highlighting the importance of successful future financing and market execution.

A New Dawn in the Fight Against Nicotine Dependence

Achieve Life Sciences stands at a pivotal juncture, poised to introduce a potentially transformative treatment into the vast and critically underserved market for nicotine dependence. With an estimated 29 million adult smokers and 11 million adult vapers in the United States alone, and tobacco use claiming millions of lives globally each year while contributing to over $300 billion in annual U.S. healthcare costs, the need for more effective cessation tools is urgent. For nearly two decades, the landscape of prescription treatments has remained stagnant, leaving millions struggling against the powerful grip of nicotine, often cited as the third most addictive drug after heroin and cocaine. Achieve's lead product candidate, cytisinicline, aims to change this narrative, positioning itself as a potential new standard of care.

The competitive environment in nicotine dependence treatment is characterized by established players like Pfizer (PFE) with its product varenicline (Chantix) and companies like GlaxoSmithKline (GSK) and Johnson & Johnson (JNJ) offering nicotine replacement therapies (NRTs). While these companies possess significant scale, extensive distribution networks, and substantial financial resources, their existing products often face limitations in terms of efficacy, tolerability, or patient adherence. For instance, physicians have reported relatively low satisfaction with varenicline, with a significant portion of patients ultimately failing treatment, and NRTs may not offer the same level of craving reduction as receptor-targeting drugs. Achieve's strategic response is to enter this market with a differentiated product, leveraging its unique technological foundation to address the shortcomings of current options.

At the core of Achieve's potential lies cytisinicline, a plant-based alkaloid derived from the seeds of certain plant species. This molecule exhibits a high binding affinity to the nicotinic acetylcholine receptor, the same target as nicotine. Its proposed mechanism of action involves both reducing the severity of withdrawal symptoms and diminishing the reward and satisfaction associated with nicotine use. This targeted interaction is believed to contribute to cytisinicline's differentiated profile. Clinical trial data suggests tangible benefits over existing treatments, including a potentially lower incidence of side effects like nausea compared to varenicline and a greater reduction in craving severity compared to NRTs. While precise, directly comparable market share figures for all niche competitors are not publicly detailed, qualitative factors indicate that cytisinicline's profile could resonate with both patients seeking better-tolerated options and physicians frustrated with current success rates. Achieve's R&D efforts are focused on optimizing the delivery and manufacturing of cytisinicline, including exploring synthetic routes, although the commercial viability of such alternatives is still uncertain. The strategic implication of this technological differentiation is the potential to carve out a significant market share by offering a compelling alternative that addresses key patient and physician needs, thereby building a competitive moat based on efficacy and tolerability.

From Clinical Milestones to Regulatory Submission

Achieve's journey towards challenging the status quo in nicotine dependence treatment has been marked by significant clinical and regulatory progress. Building on its history, which includes the acquisition of assets related to cytisinicline from Sopharma AD, the company has invested heavily in robust clinical trials. The successful completion of two large, randomized Phase 3 trials, ORCA-2 and ORCA-3, provided substantial efficacy data for smoking cessation, demonstrating statistically significant increases in quitting rates compared to placebo.

A key requirement from the FDA for the smoking cessation NDA submission was the need for long-term safety exposure data beyond the 12-week treatment duration used in the pivotal trials. To meet this, Achieve initiated the open-label ORCA-OL study in May 2024. This trial rapidly enrolled participants from previous ORCA studies, reaching the critical milestone of 300 subjects with cumulative cytisinicline exposure for six months by January 2025. Furthermore, by April 2025, the study achieved the goal of 100 subjects with one year of cumulative exposure. These milestones are crucial, fulfilling the FDA's requirements and paving the way for the planned NDA submission. Data Safety Monitoring Committee reviews of the ORCA-OL trial have consistently reported no unexpected treatment-related adverse events and noted excellent participant adherence, reinforcing the drug's favorable tolerability profile observed in earlier studies.

Beyond smoking cessation, Achieve is also actively developing cytisinicline for the growing public health crisis of vaping dependence. In July 2024, the FDA granted Breakthrough Therapy designation for this indication, a significant step that promises expedited development and review processes through enhanced interaction with the agency. An End-of-Phase 2 meeting in December 2024 resulted in FDA agreement on a proposed single Phase 3 study design (ORCA-V2) and confirmed that the safety data from the ongoing ORCA-OL trial would be sufficient to support a future supplemental NDA for vaping cessation. This strategic approach allows Achieve to leverage existing safety data and focus resources on the pivotal smoking cessation NDA while laying the groundwork for expanding the label to address the unique challenges of quitting e-cigarettes, an area with no currently approved pharmacotherapies.

Financial Realities and Strategic Outlook

Despite the promising clinical and regulatory advancements, Achieve operates within the challenging financial realities of a late-stage biotechnology company. The company has not generated revenue from product sales to date and has incurred significant recurring losses since inception, resulting in an accumulated deficit of $218.4 million as of March 31, 2025. Operating expenses increased in the first quarter of 2025 to $12.9 million, up from $5.98 million in the same period of 2024, driven primarily by the costs associated with the fully enrolled ORCA-OL trial and increased general and administrative expenses, including commercial launch preparation activities. Net cash used in operating activities was $11.1 million for the three months ended March 31, 2025.

As of March 31, 2025, Achieve held $23.2 million in cash, cash equivalents, and marketable securities. While the company maintains a positive working capital balance of $17.9 million, substantial doubt exists regarding its ability to continue as a going concern without securing additional financing. Management explicitly states that current resources are insufficient to fund planned operations for the next 12 months, necessitating substantial additional capital through equity, debt, or strategic partnerships. The company successfully refinanced its debt facility with SVB in July 2024, securing up to $20 million in convertible term loans, with tranches tied to milestones like NDA acceptance. As of March 31, 2025, the principal amount of debt outstanding was $10.0 million. This debt, while providing capital, also introduces financial risk through servicing costs, floating interest rates, and restrictive covenants, including a requirement to hold substantial cash with SVB. Recent financing activities, including a $45.0 million public offering in June 2025, are critical steps in extending the company's financial runway and supporting its near-term objectives.

The strategic outlook is firmly centered on the planned NDA submission for smoking cessation in June 2025, which is expected to trigger a 12-month review period by the FDA. Following potential approval, Achieve is preparing for a commercial launch in 2026. The commercial strategy is evolving towards an innovative, cost-effective digital-first model, aiming to efficiently target high-volume prescribers and motivated patients in a healthcare environment with limited traditional access. Initial launch efforts will focus on foundational activities like establishing distribution channels, finalizing packaging and labeling, and engaging with payers to secure favorable access and reimbursement, acknowledging that the initial sales ramp is anticipated to be slow. Looking further ahead, the company plans to initiate the Phase 3 ORCA-V2 trial for vaping cessation in the first half of 2026, contingent on funding availability. Achieve is also exploring the potential role of cytisinicline in reducing the burden of smoking-related comorbidities, particularly COPD, and is open to strategic partnerships to explore these broader indications and ex-U.S. markets, while maintaining focus on the core U.S. nicotine dependence opportunity.

Conclusion

Achieve Life Sciences stands at the precipice of potentially disrupting the nicotine dependence treatment market with cytisinicline, a differentiated product candidate backed by positive Phase 3 data and a favorable tolerability profile. The imminent NDA submission for smoking cessation represents a critical near-term catalyst, potentially unlocking a significant commercial opportunity in a market desperate for new, effective options. The company's strategic focus on both smoking and vaping cessation, coupled with an innovative commercial approach, positions it to address the evolving landscape of nicotine addiction.

However, the path forward is not without considerable risk. The company's financial viability hinges on its ability to secure substantial additional funding, and the success of cytisinicline is ultimately dependent on navigating the complex regulatory approval process, achieving market acceptance, and overcoming competitive pressures from established players and alternative cessation methods. While the technological advantages of cytisinicline offer a compelling value proposition, successful execution of the commercial strategy and securing adequate reimbursement will be paramount to translating clinical success into financial sustainability. Investors will be closely watching the outcome of the NDA review and the company's ability to strengthen its financial position to support its ambitious development and commercialization plans.