Shelby

Shelby asked if the HAE program was discussed with the FDA during the clinical hold resolution for the ATTR program, and what efficacy bar payers have indicated to avoid coverage pushback for lonvo-z.

Answer

President and CEO John Leonard clarified that the FDA treated HAE and ATTR programs distinctly, and the HAE program was not part of the clinical hold discussions. Edward Dulac reported encouraging discussions with payers who recognize the unmet need and value of a one-time therapy like lonvo-z. He noted that while no specific price was discussed, payers understand the strong value proposition. The efficacy bar for existing LTPs is in the 80s for attack rate reduction and around 60% for attack-free rates, which lonvo-z aims to be competitive with.

Shelby asked if the HAE program was discussed with the FDA during conversations about the TTR clinical hold, and what efficacy bar payers have indicated to avoid coverage pushback for lonvo-z.

Answer

President and CEO John Leonard clarified that the FDA has treated the HAE and TTR programs as distinct, and the HAE program was not a subject of discussions related to the TTR hold. EVP and CFO Edward Dulac noted encouraging payer discussions, with payers recognizing the unmet need and value of a one-time therapy. He mentioned that current HAE therapies achieve attack reduction rates in the 80s and attack-free rates around 60%, and Intellia expects lonvo-z to be highly competitive with these figures, offering a strong value proposition for young patients facing decades of high-priced therapy.

Shelby, on behalf of Luca Issi from RBC Capital Markets, asked about the increase in total vaso-occlusive crises (VOCs) from 6 at the ASH presentation to 9 today (including safety follow-up) and whether this modestly decreases confidence in the drug's ability to lower VOCs in a pivotal trial.

Answer

Alex C. Sapir (President and CEO) and Iain Fraser (SVP of Early Development) clarified the VOC numbers, explaining that 6 VOCs were observed in 5 patients during the 12-week treatment period, with an additional 3 during safety follow-up, totaling 9. Fraser emphasized that the study is short, patients are not at steady state, and given the severe baseline population, VOCs during early treatment are not unexpected. Dr. Martin Steinberg (Professor of Medicine, Boston University) dismissed the small increase as insignificant, stating that based on decades of understanding, increased HbF levels will lead to reduced events, and one patient in a small, short study means nothing for ultimate efficacy.

Shelby inquired about the increase in total VOCs from six at the ASH presentation to nine today (including safety follow-up), asking if this modestly decreases confidence in the drug's ability to lower VOCs in a pivotal trial.

Answer

Iain Fraser, SVP of Early Development, clarified the VOC numbers, explaining that six VOCs were observed in the PD analysis set during the 12-week treatment, with an additional three during safety follow-up, totaling nine. He stated that the increase from ASH (different data cut) does not change their view, as it's a short study, patients are not at steady state, and the population is severe. Dr. Martin Steinberg, Professor of Medicine, Pediatrics, Pathology, and Laboratory Medicine, added that one patient's data in a short period means 'absolutely nothing for the ultimate efficacy of the agent,' given the expected relationship between increasing HbF and decreasing events.

Shelby inquired about the rationale for higher tebapivat dosing in lower-risk MDS compared to sickle cell disease, and the read-through from the thalassemia label and REMS program to sickle cell, impacting commercial opportunity expectations.

Answer

Sarah Gheuens, Chief Medical Officer and Head of R&D, explained that higher tebapivat doses in MDS are due to faster drug metabolism in MDS patients, a difference not observed in sickle cell patients who metabolize it similarly to healthy volunteers. She added that the sickle cell program did not show the same observations as thalassemia, so a REMS is not expected, aligning more with the PK deficiency program. Tsveta Milanova, Chief Commercial Officer, affirmed a meaningful commercial opportunity in sickle cell disease, noting that the team's successful execution of the thalassemia REMS provides a solid foundation if a similar program were needed.

Shelby asked about the rationale for dosing tebapivat higher in lower-risk MDS compared to the phase II for sickle cell disease, and whether the ACTIVASE label and REMS program for thalassemia would have any read-through to sickle cell, potentially changing internal commercial expectations.

Answer

Chief Medical Officer and Head of Research and Development Dr. Sarah Gheuens explained that MDS patients metabolize tebapivat faster than healthy volunteers or sickle cell patients, necessitating higher doses (10mg, 15mg, 20mg) in the phase IIB trial for MDS, whereas sickle cell patients are similar to healthy volunteers. She also stated that the sickle cell program did not have the same observations as thalassemia, so a REMS is not anticipated, similar to PK deficiency. Chief Commercial Officer Tsveta Milanova added that if a REMS were required for sickle cell, the team's successful execution with thalassemia's REMS provides a solid foundation, and the commercial opportunity for sickle cell remains meaningful.

Shelby asked about the loss of exclusivity for Setrusumab, specifically regarding foundational IP expiring in 2028 and whether additional IP estate could extend protection beyond that timeframe.

Answer

Emil Kakkis, CEO and President, highlighted that orphan drug designation provides protection well past 2030. He also mentioned that biologics rarely face typical loss of exclusivity challenges and that additional IP related to discoveries in chronic treatment are being developed, positioning the program well for future protection.