LFG316, had been studied in seven patients with transplantation-associated microangiopathy. Due to low confidence of clinical benefit, this study was closed.

This was a randomized, SoC-controlled, open-label, multi-center study in patients with TAM after hematopoietic precursor cell transplantation (HPCT) .

Study consisted of up to 28 days of screening period, 16 weeks treatment period that can be extended to 45 weeks.Approximately 40 patients was to be randomized to receive SoC or LFG316 plus SoC. Patients was included in the study if they have diagnosis of TAM and poor prognostic markers. This trial was terminated: LFG316, a monoclonal antibody inhibitor of complement factor 5 (C5), had been studied in seven patients with transplantation-associated microangiopathy (TAM). Due to low confidence of clinical benefit, this study was closed

This was a randomized, SoC-controlled, open-label, multi-center study in patients with TAM after hematopoietic precursor cell transplantation (HPCT). Study consisted of up to 28 days of screening period, 16 weeks treatment period that can be extended to 45 weeks, 36 weeks follow up, and end of study visit (EOS) at week 52. Duration of follow up depended on duration of treatment. Patients who are treated for more than 41 weeks will proceed directly to EOS visit.

Approximately 40 patients was to be randomized to receive SoC or LFG316 plus SoC. Patients was included in the study if they have diagnosis of TAM and poor prognostic markers.

Patients showing worsening of disease after two weeks of treatment or showing no response at week 4 or any time after will be considered failures and can be switched to receive the alternative treatment (SoC or LFG316). Patients can only switch treatment arms once.

Inclusion Criteria:

1. Written informed consent/assent before any study-specific screening procedures. For pediatric patients, consent will be obtained from parent(s) or legal guardian(s) and the signature of at least 1 parent or guardian will be required. Investigators will also obtain assent of patients according to local, regional or national guidelines.

2. Patients after allogeneic stem cell transplantation from a related or unrelated, HLA-matched or mismatched donor with the diagnosis of transplant related microangiopathy. Patients having received any of the following stem cell sources are eligible: G-CSF mobilized peripheral blood stem cells, bone marrow, umbilical cord blood.

3. Male and female TAM patients ≥ 2 years old at the time of first dose administration. Patients < 12 years old can only be included in the study after first IA has shown that it is safe and well tolerated in patients ≥ 12 years old (Section 3.5).

4. The presence of TAM as per below diagnostic criteria at baseline (or screening if baseline visit is skipped). All the criteria have to be met for the patients included in the study:

   • Elevated lactate dehydrogenase (any elevation above normal range)
   • Thrombocytopenia with platelet count < 50x10e9/L or more than 50% decrease in platelet count from the highest value achieved after transplant
   • Anemia below lower limit of normal or anemia requiring transfusion support as per center standard
   • Schistocytes on peripheral blood smear (>2 per HPF) OR histologic evidence of microangiopathy
   • Absence of coagulopathy (no uncompensated disseminated intravascular coagulation, DIC) at screening

5. The presence of TAM high risk features at baseline (or screening if baseline visit is skipped): Patients ≤ 16 years must have a Lansky score of ≤ 70 and patients > 16 must have Karnofsky score ≤ 70% and/or proteinuria (> 30 mg/dL) measured in two urine spot analyses.

6. Hypertension, defined for adults by SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg at baseline (or screening if baseline visit is skipped), and for pediatric patients by blood pressure greater than the 95th percentile for age, sex, and height (see Table 16-1). Additionally, patients who were started on antihypertensive medication after HSCT or who have received additional antihypertensive medication after HSCT will be eligible, even if they don't have elevated blood pressure.

7. Able to receive antibiotic prophylaxis against N. meningitides for the duration of the study.

8. Meningococcal vaccine(s) prior to LFG316 treatment if prior vaccination cannot be confirmed. The choice of vaccine(s) should take into account the serotypes prevalent in the geographic areas in which study patients will be enrolled. In case vaccination is not possible or will result in an unfavorable risk benefit ratio as judged by the investigator, vaccination can be postponed until deemed likely to be effective.

9. Patients <18 years old should receive vaccination for the prevention of S. pneumoniae and H. influenzae type b prior to LFG316 administration. In case vaccination is not possible or will result in an unfavorable risk benefit ratio as judged by the investigator, vaccination can be postponed until deemed likely to be effective.

10. Weight of at least 10kg.

Exclusion Criteria:

1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or even longer if required by local regulations. Concomitant investigational treatment, including treatment in the context of a clinical trial with marketed drugs (off-label) may be acceptable but requires approval by the sponsor on the case by case basis.

2. Known hypersensitivity to any constituent of the study medication.

3. Patients with steroid refractory graft versus host disease (SRGvHD). SRGvHD is defined as progression (=increase in overall grade) after 5 days on ≥2mg/kg methylprednisolone or equivalent OR no improvement (no decrease in overall grade) after 10 days on ≥ 2mg/kg methylprednisolone or equivalent. If patients are receiving steroids for GvHD prophylaxis as per center standard, progression after 5 days and no response after 10 days after doubling the steroid dose will be regarded as steroid refractory.

4. Patients with ALT > 10x ULN at screening.

5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (at screening or baseline).

6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 45 days after stopping study medication. Highly effective contraception methods include:

   • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
   • Female sterilization (have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
   • Male sterilization (at least 6 m prior to screening). The vasectomized male partner should be the sole partner for that subject.
   • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
   • In case of use of oral contraception women should have been stabile on the same pill for a minimum of 3 months before taking study treatment.

7. Sexually active males unwilling to use a condom during intercourse while taking drug and for 45 days after stopping investigational medication. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Male patients should not father a child in this period.

8. Positive HIV (ELISA and Western blot) test result (checked at screening). Historical local data will be acceptable if it the test was done within one month before start of HSCT conditioning and not more than 3 months before study visit 3.

9. A positive Hepatitis B surface antigen or Hepatitis C test result at screening. Historical local data will be acceptable if it the test was done within one month before start of HSCT conditioning and not more than 3 months before study visit 3.

10. Patients with any severe, progressive or uncontrolled acute or chronic medical condition (such as uncontrolled infectious disease or sepsis) or clinical laboratory abnormalities that in the investigator's opinion would make the patient inappropriate for entry into this study (at screening or baseline).

11. Patients with proven TTP as per historical data (as defined by ADAMST13 activity test) and if already available results of ADAMST13 test done at screening.

12. Patients previously treated with eculizumab for TAM.

13. Patients with known or suspected hereditary complement pathway deficiency. This exclusion criterion is not applicable to patients with complement pathway abnormalities/upregulation known to be associated with increased risk of transplant associated microangiopathy

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Adverse events are collected from First Patient First Visit (FPFV) 21-April-2016 until Last Patient Last Visit (LPLV) 30-June-2017. All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to 1 year.

Three patients died during the study. One patient from the LFG316 only group died due to sepsis that was considered related to the study drug per Investigator assessment. Two patients who switched from SoC to LFG316 died 5 and 9 days after switching, one due to respiratory failure and one due to thrombotic microangiopathy. However,for one patient the reason for discontinuation was reported as AE instead of death.