FDA Signals Flexibility with Recent Single-Arm Approvals

On January 12th, FDA approved Zycubo (copper histidinate) injection as the first treatment for Menkes disease in pediatric patients.  Menkes disease is a rare, congenital X-linked genetic disorder characterized by impaired copper absorption, leading to severe copper deficiency, progressive neurologic deterioration, and death in early childhood.  The estimated incidence of Menkes disease is approximately 1 in 100,000 live births.

Zycubo is a bioavailable copper replacement therapy that is administered as a subcutaneous injection to deliver copper in a form that bypasses the impaired gastrointestinal absorption in patients with Menkes disease.  FDA approved Zycubo based on evidence from single-arm clinical trials compared to external control groups.

Hyman, Phelps & McNamara, P.C.’s Mark Schwartz, Richard Lewis and Frank Sasinowski were honored to have assisted on the path to approval of this therapy.

On December 23, 2025, FDA approved Omeros’s Yartemlea (narsoplimab-wuug) for the treatment of adult and pediatric patients 2 years of age and older with hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), another example of reliance on single-arm evidence of effectiveness for an ultra-rare condition.

TA-TMA is a life-threatening complication of transplantation caused by endothelial injury, which leads to a microangiopathic hemolytic anemia, thrombocytopenia, and renal damage, which can lead to death.

Until now, there had been no specific treatment options for TA-TMA.  Clinical management had largely been supportive, focusing on controlling hypertension, providing transfusion support, modulating immunosuppressants, and dialysis.

Yartemlea is a monoclonal antibody that targets mannan-binding lectin-associated serine protease-2 (MASP-2), a key enzyme in the lectin pathway of the complement system.  By inhibiting MASP-2, Yartemlea blocks downstream lectin pathway activation without affecting the classical or alternative complement pathways.  Prior to Yartemlea’s approval, FDA had not approved any inhibitor of the lectin pathway, so this represented a challenging first-in-class approval for a drug with a novel mechanism of action.

Yartemlea was approved on the basis of a single-arm, open-label study involving 28 adult patients with TA-TMA following hematopoietic stem cell transplantation, as well as patient-level data from 19 adult and pediatric patients with TA-TMA enrolled in an expanded access program (EAP).

The primary efficacy endpoint was TMA response, defined as improvement in two laboratory TMA markers—lactate dehydrogenase (LDH) levels and platelet counts—together with either improvement in organ function or achievement of transfusion independence.  All patients met internationally harmonized criteria for high-risk TA-TMA, which is associated with poor prognosis and high mortality.  For the primary endpoint, response rates were 61% and 68% in the TA-TMA Study and EAP, respectively, and 100-day survival was approximately 73% in both groups.

For a first-in-class therapeutic with a novel endpoint and no regulatory precedent, it can be challenging to assess the clinical meaningfulness of results of a single-arm trial.  Although not mentioned in the drug labeling (the review materials are not yet available), Omeros’s press release refers to an external control cohort, citing a publication that compares survival in narsoplimab-treated patients to those in a registry.  The extent to which FDA’s review relied on this external control to contextualize the data is unclear.  The publication notes that mortality in narsoplimab-treated patients was reduced by more than 60% compared to the external control; presumably, these data were important to FDA in their assessment of the applicant’s uncontrolled data.  The finding of improvement in survival is always of paramount importance, regardless of whether or not it is the primary endpoint.

Notably, the approval was in adult and pediatric patients despite the fact that the only pediatric patients evaluated were in the EAP, demonstrating the potential value of such a program to a sponsor.  It is rare to see data from an EAP in Section 14 of drug labeling; in this case, there were 19 patients with available patient-level data out of the 221 patients in the program (~9%).  Although this was a small fraction of the total number of patients in the EAP, it is notable.  FDA’s recent pronouncement may facilitate even greater acceptance of such real-world evidence in the future.

Several of us from Hyman, Phelps & McNamara, P.C. were honored to have assisted Omeros on Yartemlea over many years.  With appropriate exercise of FDA flexibility, we are glad to have contributed to treatment options for adult and pediatric patients with TA-TMA and their loved ones.

We applaud FDA on the flexibility applied in these disease settings where randomized controlled trials present substantial feasibility challenges.  We look forward to the publication of FDA’s Summary Basis for Approval for the Zycubo NDA and the Yartemlea BLA, which should provide valuable insight into how the Agency determined that these applications met the effectiveness standard.