Natalizumab SC Similar to IV Every 4 Weeks for MS

Susan Jeffrey

June 22, 2015

BERLIN, Germany — Results of a randomized comparison suggest that subcutaneous administration (SC) of 300 mg of natalizumab (Tysabri, Biogen) is just as effective at 4 weeks as the currently used intravenous (IV) route, providing patients with multiple sclerosis (MS) a potentially more convenient method of delivery. However, the company recently announced it has no plans at this time to pursue the SC product.

Results of the REFINE trial, comparing three different SC vs IV regimens of natalizumab, were presented by Maria Trojano, MD, Department of Neurological and Psychiatric Sciences, University of Bari, Italy, here at the first Congress of the European Academy of Neurology (EAN) meeting.

The other four arms, all looking at regimens given every 12 weeks rather than 4, were stopped because of breakthrough disease activity in these groups, Dr Trojano noted.

During the question period, coauthor Luigi Maria Grimaldi, MD, from Unità Operativa Neurologia, Fondazione Istituto San Raffaele G. Giglio di Cefalù, Italy, remarked on the Biogen decision not to pursue commercialization of this subcutaneous product, a decision that he described as "making the only positive result of this trial basically useless."

Dr Trojano replied that she agreed heartily with his opinion and passed the query to another coauthor, Daniel Mikol, MD, PhD, senior medical director at Biogen.

"Biogen has done a review of all of its programs and does it periodically and regarding subcutaneous development of Tysabri, in this case it was felt after getting feedback from physicians and patients around the world, a subcutaneous [form] wouldn't meet any significant unmet need over what we have with intravenous natalizumab," Dr Mikol said, "so the decision was made not to pursue the development of this formulation in MS."

REFINE Trial

In patients with relapsing-remitting MS, 300 mg natalizumab given intravenously every 4 weeks significantly reduced clinical relapse rates, MRI evidence of disease activity, and confirmed progression of disability relative to placebo at 2 years, and this benefit appears to be maintained over the long term in postapproval observational studies, Dr Trojano noted.

It was not known though whether alternative dosing regimens or routes of administration could maintain these benefits while providing a lower exposure to the drug, which carries a risk for progressive multifocal leukoencephalopathy (PML), and more convenience for patients.

REFINE was a parallel-group exploratory study of 290 clinically stable patients with relapsing-remitting MS previously treated with natalizumab for 12 months or longer who were blinded to dose and frequency but not to administration route. Patients were randomly assigned to one of six natalizumab regimens over 60 weeks, 300 mg IV every 4 weeks, 300 mg SC every 4 weeks, 300 mg IV every 12 weeks, 300 mg SC every 12 weeks, and then two additional arms exploring a lower dose of 150 mg IV or 150 mg SC given every 12 weeks.

The primary endpoint was the sum of combined unique active MRI lesions, including new gadolinium-enhancing or new/newly enlarging T2 lesions, over 60 weeks of treatment. Additional endpoints were annualized relapse rates, pharmacokinetics (natalizumab concentration), pharmacodynamics (α4-integrin saturation), immunogenicity (anti-natalizumab antibodies), and serious adverse events.

Patients were offered rescue therapy with high-dose corticosteroids or open-label natalizumab at the standard 300-mg dose given via the IV route every 4 weeks if they had evidence of MRI disease activity, acute clinical relapse, or confirmed 3-month progression on the Expanded Disability Status Scale.

During the randomized treatment period, however, the data and safety monitoring committee for the trial recommended closure of the 12-week arms because of increased disease activity. "The first arm closed was the 150-mg subcutaneously every 12 weeks, when about 34% of patients met rescue criteria," Dr Trojano said. "Overall, less than 20% of patients in each of the four every-12-week treatment arms were exposed to the planned 15 doses, in comparison to 76% of patients in each of the two every-4-weeks arms. The two every-4-weeks arms completed the randomized period."

For the primary endpoint, at week 60, the number of combined, unique, active lesions was similar in the two groups receiving treatment every 4 weeks, while all four groups treated at 12 weeks showed an increase in disease activity, leading to their early closure.

Table 1. Mean Cumulative New Lesions on MRI by Treatment

Treatment Group Mean Cumulative New Gadolinium-Enhancing and New/Newly Enlarging T2 Lesions (n)
300 mg IV every 4 wk 0.23
300 mg SC every 4 wk 0.02
300 mg IV every 12 wk 3.84
300 mg SC every 12 wk 3.08
150 mg IV every 12 wk 6.09
150 mg SC every 12 wk 6.44

 

The proportion of patients who met MRI rescue criteria was very low, about 2% in the two every-4-weeks groups, but ranged from 43.5% up to 70.3% for the every-12-weeks groups.

Similarly, annualized relapse rates were low and similar in the every-4-weeks groups vs the every-12-weeks groups. However, the overall time during which events could be observed in the four 12-week groups varied because the number of evaluable patients in those groups was decreasing as they met rescue therapy criteria, Dr Trojano said.

Table 2. REFINE: Annualized Relapse Rates by Treatment

Treatment Group Annualized Relapse Rate
300 mg IV every 4 wk 0.07
300 mg SC every 4 wk 0.08
300 mg IV every 12 wk 0.20
300 mg SC every 12 wk 0.30
150 mg IV every 12 wk 0.47
150 mg SC every 12 wk 0.18

 

Trough serum concentrations remained stable and similar to baseline concentrations in the every-4-week groups, but they decreased by week 12 and remained low or below the limit of quantification throughout the study in the four every-12-week groups. Similar results were seen for trough α4-integrin saturations, which remained high in both every-4-week groups and low in the every-12-week groups.

Anti-natalizumab antibodies were not seen in the two 300-mg every-4-week arms, but persistent antibodies were seen in one patient in the 300-mg IV every-12-weeks groups and one in the 150 mg IV every-12-weeks group.

Serious adverse events were consistent with natalizumab's known safety profile, she said. One or more serious adverse events were seen in 23 patients (8%), and of these, seven had serious events leading to withdrawal from the study. One case of fatal metastatic adenocarcinoma was reported in the 300 mg SC every-12-weeks group; the patient had a family history of the disease and the death was considered unrelated to study treatment, Dr Trojano noted.

One case of PML was seen in the 300 mg IV every 4-weeks-arm group, in a patient positive for anti–JC virus antibodies, no history of immunosuppressant use, and an exposure to natalizumab of 34 infusions.

"So in conclusion, we can say that the results of this study suggest that an interval between natalizumab infusions of 12 weeks was not able to control the MRI and clinical disease activity in relapsing-remitting patients," Dr Trojano said. "The other important point; this study demonstrated that natalizumab 300 mg subcutaneously administered every 4 weeks had similar efficacy, clinical and MRI efficacy, also pharmacokinetics, pharmacodynamics and immunogenicity, to the standard dose used in clinical practice."

During the discussion, Giancarlo Comi, MD, professor of Neurology, Vita-Salute San Raffaele University, Milan, Italy, noted that although 3 months was clearly too long between treatments, he asked about any evidence of reactivation on clinical or MRI data before the third month, "meaning that even with a 2-month period, you start to be at risk, which is again a quite practical suggestion for us."

Dr Trojano said that pharmacokinetic and pharmacodynamics data demonstrated that by 3 months, the values declined and remained low, but disease reactivation was "very early, in the first 6 to 8 weeks, and as a consequence these arms were closed early."

Dr Grimaldi added that his group and others have reported that among patients with unintentional delay between doses, disease activity recurred after about 8 weeks. "So the idea would be that probably you can delay 7, up to 8 weeks," he said, and suggested a study should be done with a treatment interval of up to 2, not 3, months.

The REFINE study was sponsored by Biogen. Dr Trojano reports she has served on scientific advisory boards for Biogen, Merck Serono, and Novartis; has received speaker honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi, and Teva; and has received research grants from Biogen, Merck Serono, and Novartis.

Congress of European Academy of Neurology (EAN). Abstract O1217. Presented June 20, 2015.

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