Twist in Protagonist story as FDA seeks to rescind breakthrough nod 'based on observed malignancies'

The FDA gave Protagonist Therapeutics’ rusfertide breakthrough designation last year. Now, the agency wants to take it back “based on observed malignancies,” triggering a 30% drop in Protagonist’s stock as investors scrambled to figure out the implications of the news.

Protagonist broke the news in a brief financial regulatory filing, revealing the FDA sent a letter indicating its intent to rescind the breakthrough-therapy designation for hepcidin mimetic rusfertide in the red blood cell disorder polycythemia vera “based on observed malignancies, in follow-up to the FDA clinical hold imposed on September 16, 2021.” The stock fell 30% to around $18 following the news. 

In response, Protagonist sent a request to meet with the FDA and a briefing document making the case for the retention of the breakthrough status. Rusfertide’s orphan-drug and fast-track statuses remain in place, and Protagonist is sticking to its development plan and phase 3 timeline. 

After receiving the FDA letter, Protagonist updated its corporate presentation with additional details of the cancer cases seen in recipients of rusfertide. Across all indications, 168 patients have received the drug. Protagonist has seen eight cancer cases in seven of the subjects, inclusive of cases confirmed as preexisting. All patients with treatment-emergent skin cancers had prior episodes of skin cancer.

Among the 89 polycythemia vera patients treated with rusfertide, Protagonist has seen six events, three of which were observed during re-enrollment skin exams, in five subjects. Of the cases, Protagonist said “one confirmed pre-existing” and “one with 2 dermatologic events”. The other three subjects were all taking “other therapeutic agents with known carcinogenicity risks (e.g., hydroxyurea, ruxolitinib).” Protagonist listed disease progression, being over 60 years old, skin type and cumulative sun exposure as other confounding variables.

Protagonist presented the safety results alongside the findings of an analysis of claims data for 28,000 polycythemia vera. Around 10% of the patients had at least one diagnosis of skin cancer after their initial polycythemia vera diagnosis.  

In its phase 2 trial, Protagonist established stopping rules aligned to the background rate of cancer in the patient population. The observed cases never reached the threshold. Protagonist is using the same rules in its phase 3 clinical trial, which has now activated sites and is scheduled to complete enrollment in the first half of next year. 

Protagonist is developing rusfertide for use in the 60% of patients with moderate burden polycythemia vera. PharmaEssentia’s Besremi, which won FDA approval late last year, may find a role in the treatment of the population targeted by Protagonist. Incyte’s Jakafi is available for people with higher burdens, and infrequent blood draws largely address the needs of low-burden patients.