Lemtrada For Multiple Sclerosis – Just The Facts
The debate over the FDA’s reluctance to approve alemtuzumab (brand name Lemtrada, an anti-CD52 antibody, aka Campath) continues, with heated opinions being expressed, mainly by those that want Lemtrada approved. We note without comment that a fair number of the FDA’s fiercest critics have exposure to stock warrants tied to this drug’s commercial success. The FDA stance seems to some to be overly tough, particularly as the drug has been approved for MS in other markets, notably the often risk-adverse EU.
I’ve been puzzled by this debate, and more puzzled since it is taken place more of less without discussion of the Phase 3 clinical trial data. Granted this is hard for some of us to get. I do not have the FDA documents for example. The clinical trial data is behind a paywall at the Lancet, and I’m just annoyed enough at the price to resist paying it. So let’s see what we can do using just publicly available information.
The Lancet summaries are available. Here is the first one (via http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61769-3/abstract):
Background
The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial.
Methods
In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18—50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348.
Findings
187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32—0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40—1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma.
Interpretation
Alemtuzumab’s consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here.
What is this telling us?
1) this is a 2-year trial in previously untreated MS patients; the dose regimen is 12 mg daily for 5 days and then at 12 months a second regimen of 12 mg daily for 3 days
2) the active comparator is Rebif, a beta-interferon
3) there was a benefit seen in relapse rate: about 20% fewer patients had a relapse in the alemtuzumab arm as compared to the Rebif arm
4) there was no improvement in time to 6-month sustained accumulation of disability
5) 90% of alemtuzumab patients had infusion reactions but only 3% on these were serious
6) Over 60% of patients experienced infections, over 60% developed cutaneous herpes, over 60% developed thyroid associated adverse events, and 1% developed immune thrombocytopenia.
Summary: alemtuzumab hit one of its primary endpoints, missed the second, and had a challenging toxicity profile.
How about that second paper in Lancet? Well, here is the abstract (via http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61768-1/abstract)
Background
The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.
Methods
In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18—55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.
Findings
202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39—0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38—0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.
Interpretation
For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab’s main adverse effect of secondary autoimmunity.
Again, what is this telling us?
1) this is a 2-year trial in patients with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer; the dose regimen is 12 mg or 24 mg daily for 5 days and then at 12 months a second regimen of 12 mg or 24 mg daily for 3 days. The 24 mg dose was discontinued.
2) the active comparator was Rebif, a beta-interferon
3) there was a benefit seen in relapse rate: 16% fewer patients experienced a relapse on alemtuzumab as compared to Rebif
4) importantly, 65% of patients were relapse free at 2 years
5) there was an improvement in time to 6-month sustained accumulation of disability
6) 90% of alemtuzumab patients had infusion reactions
7) 77% of alemtuzumab patients experienced infections, 16% developed thyroid associated adverse events, and 1% developed immune thrombocytopenia.
Summary: alemtuzumab hit both of its primary endpoints and had a challenging toxicity profile.
How does this efficacy compare to other treatments? The reduction in annualized relapse rate (ARR) lies between the beta-interferons or copaxone and highly efficacious drugs like natalizumab (Tysabri), daclizumab or fingolimod (Gilenya). The following data are taken from the UPTODATE website, last updated January 15, 2014.
(http://www.uptodate.com/contents/treatment-of-relapsing-remitting-multiple-sclerosis-in-adults)
| agent | trial(s) | ARR (across doses) | ARR/comparator | SAD met? |
|---|---|---|---|---|
| dimethyl fumarate (Tecfidera) | CONFIRM | 24% | 40% (placebo) | trend/ns |
| dimethyl fumarate (Tecfidera) | DEFINE | 18% | 36% (placebo) | yes |
| fingolimod (Gilenya) | FREEDOMS | 17% | 40% (placebo) | yes |
| fingolimod (Gilenya) | TRANSFORMS | 18% | 36% (interferon beta 1-a) | not assessed |
| alemtuzumab (Lemtrada) | CARE-MS I | 22% | 40% (interferon beta 1-a) | no |
| alemtuzumab (Lemtrada) | CARE-MS II (relapsed patients) | 35% | 53% (interferon beta 1-a) | yes |
| natalizumab (Tysabri) | AFFIRM (relapsed patients) | 26% | 81% (placebo) | yes |
| natalizumab (Tysabri) | SENTINEL (relapsed patients) | 38% | 82% (placebo) | yes |
So it seems to me that we have an efficacy/toxicity profile on a par with fingolimod and natalizumab. Of note, the UPTODATE profile concludes the section of alemtuzumab as follows:
“Although its precise role in the management of RRMS is not yet settled, alemtuzumab will probably be used as a second-line agent for patients with RRMS who have an inadequate response to treatment with interferons and glatiramer. The role that alemtuzumab will play in the context of other newer MS disease-modifying agents (eg, fingolimod, teriflunomide, and BG-12) is still undefined. Alemtuzumab therapy requires monitoring for infusion reactions and prophylaxis for herpes virus infections and Pneumocystis jirovecii (PCP) pneumonia during treatment and for several weeks after treatment. Prolonged surveillance for bone marrow suppression, infections, and autoimmune disorders such as immune thrombocytopenia is also necessary.”
So that seems to be the heart of the problem, that the comparison to the most relevant medications is not well defined and you have a lot of toxicity that requires monitoring.
As the title said, “just the facts” – I don’t aim to draw conclusions here but just lay out the data so when we see arguments pro or con for this drug, we have a place to turn to look at the data.