FDA Grants Breakthrough Therapy Designation to AlphaMedix for Gastroenteropancreatic Neuroendocrine Tumors

The FDA has granted breakthrough therapy designation to AlphaMedix (²¹²Pb-DOTAMTATE) for the treatment of adult patients with unresectable or metastatic, progressive somatostatin receptor (SSTR)–expressing gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who have not previously received peptide receptor radioligand therapy (PRRT).¹ AlphaMedix represents the first Targeted Alpha Therapy to receive this designation.

The decision is based on findings from phase 1 and ongoing phase 2 trials evaluating the safety and efficacy of AlphaMedix. In the phase 1 dose-escalation trial (NCT03466216), AlphaMedix treatment was well tolerated and generated an overall response rate (ORR) of 62.5% per RECIST v1.1 criteria in patients with GEP-NETs who were naive to PRRT with lutetium Lu 177 dotatate (Lutathera; n = 20).¹ Data from this trial, which were presented at the 2021 ASCO Annual Meeting, demonstrated that the most common any-grade adverse effects (AEs) included fatigue (35%), alopecia (30%), hyperglycemia (30%), lymphopenia (30%), and diarrhea (20%).² A total of 5 grade 3 AEs were reported: acute kidney injury, back pain, dysarthria, and dyspnea. No grade 4 AEs occurred, and 1 grade 5 AE was reported. Most patients who responded to AlphaMedix (n = 5) experienced significant improvements in quality of life (QOL), pain reduction, shortness of breath, and energy increases.

In the phase 2 ALPHAMEDIX02 trial (NCT05153772), AlphaMedix has already achieved the trial’s target response rate, and topline data are expected midway through 2024.¹

“The FDA’s breakthrough therapy designation underscores AlphaMedix’s potential as an innovative treatment that could redefine how patients with NETs are treated,” Ebrahim Delpassand, MD, chairman and chief executive officer of RadioMedix, stated in a news release. “We believe that AlphaMedix has the potential to demonstrate substantial benefit over currently FDA-approved PRRT with beta-particle emitters for patients with metastatic or inoperable SSTR-expressing GEP-NETs. The FDA’s decision is great news for patients suffering from this illness and an important milestone to expedite the development of this new therapy.”

AlphaMedix is a Targeted Alpha Therapy in phase 2 clinical development that consists of an SSTR-targeting peptide complex that is radiolabeled with lead-212 (²¹²Pb), which generates alpha particles in vivo. Alpha emitters have short path lengths and high energy, allowing them to enable specific targeting and killing of individual cancer cells with minimal toxicity to surrounding healthy tissue.

The nonrandomized, open-label, single-arm, single-center phase 1 trial enrolled patients with an ECOG performance status (PS) of 0 to 2 with histologically confirmed, SSTR-positive, unresectable or metastatic NETs who had a life expectancy of at least 12 weeks and measurable disease per RECIST v1.1 criteria.³ Patients must have exhausted all FDA-approved therapies for which they were eligible.

Determination of the dose-limiting toxicities and maximum tolerated dose of AlphaMedix served as the coprimary end points of the trial. Secondary end points included partial response or complete response per RECIST v1.1 criteria, determination of effective blood clearance and cumulative blood activity of ²¹²Pb, determination of the rate and extent of ²¹²Pb elimination in urine, and the incidence of treatment-related AEs and serious AEs per CTCAE v.4.0 criteria.

The open-label, single-arm ALPHAMEDIX02 trial is enrolling patients at least 18 years of age with unresectable or metastatic histologically confirmed NETs who have received and progressed on a somatostatin analog, have an ECOG PS of 0 to 2, and a life expectancy of at least 12 weeks.⁴ PRRT-naive patients must have documented disease progression following prior therapy within 12 months before trial enrollment, as well as 1 or more measurable disease sites per RECIST v1.1 criteria. Patients with prior PRRT exposure must have documented disease progression and 1 or more measurable disease sites per RECIST v1.1 criteria after receiving a maximum of 4 doses of 177Lu-DOTATATE/DORTATOC and received their last dose at least 6 months prior to the first day of the phase 2 trial.

The coprimary end points of ALPHAMEDIX02 are ORR per RECIST v1.1 criteria and the number of patients with treatment-related AEs per CTCAE v4.0 criteria. Key secondary end points include median progression-free survival, overall survival, time to progression, and health-related QOL.

“Receiving FDA breakthrough therapy designation for AlphaMedix is a great achievement for everyone involved and confirms the strong interest of the medical community for Targeted Alpha Therapies with ²¹²Pb,” Julien Dodet, president and chief executive officer of Orano Med, added in the news release.¹ “Based on positive results from our clinical studies to date, we are convinced that Targeted Alpha Therapies, such as AlphaMedix, will lead the next generation of radioligand therapies, providing increased cytotoxicity against cancer cells but limited toxicity to adjacent healthy cells. This recognition from the FDA reinforces Orano Med’s commitment to making innovative ²¹²Pb-based therapies available to the medical community and patients worldwide.”

References

1. RadioMedix and Orano Med receive FDA breakthrough therapy designation for AlphaMedix in gastroenteropancreatic neuroendocrine tumors first targeted alpha therapy to receive a breakthrough therapy designation. News release. RadioMedix and Orano Med. February 12, 2024. Accessed February 12, 2024. https://www.oranomed.com/en/resources/news/2024/radiomedix-and-orano-med-receive-fda-breakthrough-therapy-designation-for-alphamedixtm-in-gastroenteropancreatic-neuroendocrine-tumors
2. Delpassand E, Tworowska I, Esfandiari R, Torgue J, Hurt JD, Nunez R. Phase I dose-escalation study of AlphaMedix for targeted-alpha-emitter therapy of PRRT-naive neuroendocrine patients. J Clin Oncol. 2021;39(suppl 15). doi:10.1200/JCO.2021.39.15_suppl.4117
3. Phase 1 study of AlphaMedix in adult subjects with SSTR (+) NET. ClinicalTrials.gov. Updated August 24, 2021. Accessed February 12, 2024. https://clinicaltrials.gov/study/NCT03466216
4. Targeted alpha-emitter therapy of PRRT naïve and previous PRRT neuroendocrine tumor patients (ALPHAMEDIX02). ClinicalTrials.gov. Updated October 23, 2023. Accessed February 12, 2024. https://clinicaltrials.gov/study/NCT05153772