CINP 2024 - Plenary Lecture - Dr. Haruo Naito - Spirit of Drug Discovery

Thank you, Dan, for that excellent introduction. He covered most of my talk, so I may finish now, but I'm honored to speak at this distinguished conference. As Dan mentioned, we recently succeeded in developing lecanemab, which removes amyloid-beta protofibrils and showed clinically meaningful results. Through this journey, we learned invaluable lessons. I'll share some of them and later discuss our unique pricing approach. The origin traces back to 1992 with John Hardy's amyloid cascade hypothesis. In 2001, Lars Lannfelt discovered the Arctic mutation in Swedish families, linking protofibrils to neurotoxicity. We collaborated with academia, developed an antibody specific to protofibrils, and named it lecanemab. Phase 2 (study 201) took six years and failed at 12 months but showed significance at 18 months, teaching us the right dose (10 mg/kg biweekly), the correct target population, and that endpoints should be at 18 months. Phase 3 (Clarity AD) was the largest Alzheimer's study ever, with 1,800 patients. It showed 27% slowing of decline on CDR-SB (p=0.0005), all secondary endpoints positive, and quality of life endpoints even stronger. ARIA rates were acceptable and lower than other antibodies. Our clinical pharmacology model predicted the results with remarkable accuracy. Four success elements: academic collaboration, learning from failure, strong leadership that makes decisions and never gives up, and a visible professional team. We also persisted through failures like gamma-secretase modulators and aducanumab. We see Alzheimer's as a blue ocean now because we have the chart. For pricing, we used value-based pricing. We quantified the impact using a willingness-to-pay threshold of $200,000 per QALY gained in the US. The model showed a QALY gain of 0.64, increasing health outcomes by 17.7%. We set the annual price at $26,500 per patient, returning 60% of the total impact to society and keeping 40% as reward for innovation. Finally, our motivation for 40 years of research comes from empathy with patients through socialization programs. We believe the day Alzheimer's becomes curable will surely come.

Thank you, that's a very good question. We are now filing a dossier for maintenance dosing, which is half dosing. The initial period—one year, 18 months—is under discussion with agencies. We have solid clinical data covering 36 months showing efficacy. Since lecanemab removes one pathology of Alzheimer's and the disease is progressive, continuous treatment is beneficial. We are developing a subcutaneous auto-injector for home use. Does that answer your question?

Good question. In the phase 2 open-label extension, there was a two-year gap without treatment, and patients worsened with amyloid reaccumulation. So continuous treatment, even at lower doses, is necessary. Second, earlier intervention: we are conducting a preclinical study in people with amyloid accumulation but no symptoms, with 14,400 patients enrolled. Starting earlier should increase efficacy. Those are the solutions we have now.

The study is long-term, but enrollment is going faster than expected. We are using biomarkers substantially. We will get results in a few years.

You raise a very important point. Even for the current indication, many patients are not eligible, leading to huge disappointment. This is a serious issue for physicians in daily practice.

It is hard to understand that there is a treatment but you cannot get it, but it is true. Over time, with experience, regulations may be adjusted, and there are ways to discuss possibilities with patients.

Thank you very much, Professor. I appreciate your leadership. The target—amyloid-beta protofibrils—is a soluble oligomer with strong neurotoxicity, making it the right target. Additionally, lecanemab has a low rate of neutralizing antibodies, which is a special feature that differentiates it from other antibodies.