Happy Days are here again.
Although Novartis’s Gilenia, which is set to be the first oral disease modifying agent/drug/therapy (DMA/DMD/DMT) for Multiple Sclerosis (MS) had its priority review PDUFA (Prescription Drug User Fee Act) date pushed out to September 2010, this meeting is important because it will give us much clearer insight into what concerns the FDA may have.
The are 12 questions raised to the FDA Advisory Committee to discuss are:
1. Has the sponsor demonstrated substantial evidence of effectiveness of fingolimod for the treatment of patients with relapsing remitting multiple sclerosis to reduce the frequency of clinical exacerbations? [Voting Question]
2. Has the sponsor demonstrated substantial evidence of effectiveness of fingolimod for the treatment of patients with relapsing remitting multiple sclerosis to delay the accumulation of physical disability? [Voting Question]
3. If the answer to question #1 and/or question #2 is yes, should the sponsor be required to evaluate the effects of doses lower than 0.5 mg once daily? [Voting Question]
4. If the answer to question #3 is yes, should this be required prior to approval? [Voting Question]
5. If substantial evidence of effectiveness has been demonstrated, do you conclude that there are conditions under which fingolimod could be considered safe in use for this indication? [Voting Question]
6. First-dose effects of fingolimod include bradycardia and heart conduction abnormalities. Based on the data presented to you, should patients be required to receive the first dose in a monitored setting? [Voting Question]
7. If the answer to question #6 is yes, should that requirement apply to all patients or to a specific subset?
8. Fingolimod causes macular edema, including at the dose proposed for marketing (0.5 mg). Is routine ophthalmic examination sufficient to monitor patients treated with fingolimod? [Voting Question]
9. Fingolimod causes a gradual decline in pulmonary function that appears partially reversible. Do you believe that routine pharmacovigilance will be sufficient to mitigate the risks associated with the pulmonary toxicity of fingolimod? [Voting Question]
10. If the answer to question #9 is no, what additional monitoring or study do you recommend?
11. The sponsor has proposed to conduct a 5-year post-marketing safety study in 5000 patients to further explore the safety of fingolimod 0.5 mg under routine clinical care. Do you believe that such a study would be sufficient to address safety issues observed in this database, or do you believe that other safety studies should be required to assess specific safety concerns? If so, please identify these concerns.
12. Considering the risks and benefits, do you believe that fingolimod should be generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy? [Voting Question]
To help us sort through these question, let’s go through the poster abstracts presented at the recent Consortium of MS Centers (CMSC) Annual Meeting in San Antonio, TX.
1. 1 1. TRANSFORMS – Oral fingolimod (FTY720) vs intramuscular (IM) interferon beta-1a (IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS): clinical efficacy results.
In this trial patients received a daily oral pill and a weekly intramuscular injection, but it was double-blinded (both the patient and the team evaluating the patient) didn’t know whether she was receiving a real pill of fingolimod (at two doses – 0.5 mg and 1.25 mg) and fake (placebo) intramuscular injections or a placebo pill and real interferon beta-1a (Avonex) intramuscular injections.
The 3 arms of the study were well matched before the study and we saw a significant reduction in the annualized relapse rate (ARR) in this one year study: ARR for fingolimod 0.5 mg was 0.16 vs. fingolimod 1.25 mg at 0.2 and IM IFNB-1a at 0.33.
This means that we have a study population that looks similar to our more recent (“modern”) clinical trials in that it shows an ARR for the current injectables at about 0.33, yet we have an oral drug that beats active treatment (not simply placebo – this trial had no oral placebo + IM placebo arm) by 38 – 52%.
The data was further divided into the ARR for treatment naïve patients (0.15 vs. 0.17 vs. 0.31) and the ARR for participants who were previously treatment with a DMT (0.26 vs. 0.33 vs. 0.53). This makes a lot of sense – people who entered the study with 1 or more confirmed relapse during the previous year (or 2 or more confirmed relapses in the previous 2 years) and who had been on a DMT already, are more likely to have not responded fully to the DMT and, hence, be harder to treat with any medication, including fingolimod.
Now many patients (and neurologists) will say that an ARR of 0.33 (in patients treated with the current injectables) does not reflect the relapse rate they see in real life, so the investigators looked at he ARR for all relapses (not simply confirmed, but also unconfirmed) and that was 0.3 vs. 0.33 vs. 0.63. So, even if we liberalize the definition of a relapse, fingolimod still significantly beats Avonex in this one year trial.
Instead of looking at the relapse rate, we can also look at the proportion of participants relapse-free (after all, isn’t that what we want?) and that comes to 83% vs. 80% vs. 69%.
Not all relapses are created equally
While relapses are important, the disability they are accompanied with (not just left with) are important – so we care about the severity of the relapses as well. Although not approved by the FDA for these purposes, I believe that our DMTs not only reduce the number of relapses but also their severity. Looking at relapses requiring hospitalization, the ARR for the three groups (fingolimod 0.5 vs. fingolimod 1.25 mg vs. Avonex) was 0.022 vs. 0.039 vs. 0.077; this means that you are 71.4% less likely to need hospitalization for a relapse if you are on fingolimod 0.5 mg as compared to Avonex (49.4% for fingolimod 1.25 mg vs. Avonex).
In the RECLAIM (Relative Efficacy of repeat Course of intravenous methyLprednisolone and intramuscular ACTH in the treatment of acute relapse of multiple sclerosis after sub response to Initial course of intravenous Methylprednisolone), we (this is a Neurologique specific trial written by Dr. Kantor) are trying to see how we can reduce the need for additional courses of steroids for the treatment of MS and in the TRANSFORMS trial, taking fingolimod meant that even if you had a relapse, it was less likely that you needed steroids (ARR of 0.084 vs. 0.115 vs. 0.176).
So, of the 429 participants on fingolimod 0.5 mg vs. 420 on fingolimod 1.25 mg vs. 431 on IFNB-1a, 17.5% vs. 19.5% vs. 29.9% had a relapse and 11.2% vs. 13.1% vs. 18.3% required steroids with no hospitalization and 1.9% vs. 3.1% vs. 7% required hospitalization.
In summary, the efficacy data from TRANSFORMS (Trial Assessing Injectable Interferon vS FTY720 Oral in Relapsing-Remitting Multiple Sclerosis), demonstrated that in a one year trial, fingolimod significantly beat a currently available injectable in terms of measures of relapses. The results for fingolimod 0.5 mg vs. 1.25 mg, has led us topursue the lower 0.5 mg dose rather than 1.25 mg.
2. 2. Oral fingolimod (FTY720) vs placebo in relapsing-remitting multiple sclerosis (RRMS): 2 year efficacy results of the phase III FREEDOMS trial.
While TRANSFORMS [2302] was a one year global (including U.S.) trial comparing two dose of fingolimod to active treatment (Avonex), FREEDOMS was a two year global (ex-U.S.) trial comparing two doses of fingolimod to placebo.
As we have discussed in the past (http://bit.ly/98pGyk and http://bit.ly/dBWxrH), FREEDOMS [2301] (FTY720 Research Evaluating Effects of Daily Oral Therapi in Multiple Sclerosis) confirmed in a longer (2 year) trial that fingolimod has robust efficacy. Compared to placebo, fingolimod 0.5 mg and 1.25 mg reduced ARR by 54 – 60% (and it did so whether participants had been previously treated with a DMT or no). Compared to placebo, fingolimod 0.5 mg and f
Fingolimod 1.25 mg increased the proportion of participants who were relapse free (46% vs. 70% vs. 75%).
It’s not all about the relapses – what about disability?
Fingolimod significantly reduced the risk of disability progression by 30% – 40% (we look at 3 or 6 month confirmed Expanded Disability Status Scale or EDSS progression and the Multiple Sclerosis Functional Composite or MSFC).
3. 3. Oral fingolimod in relapsing-remitting multiple sclerosis (RRMS): MRI findings from TRANSFORMS and FREEDOMES phase III trials
So, now that we have seen the robust clinical efficacy (in terms of relapses and also some disability data) from TRANSFORMS (fingolimod vs. IM IFNB-1a) and FREEDOMS (fingolimod vs. placebo), we move on to the best (yet imperfect) surrogate marker we have, MRI.
When using MRI to compare the efficacy of treatments, we look at several aspects of the MRI – inflammatory lesions (there is Gadolinium enhancement of white matter spots when there is active breakdown of the blood brain barrier; T2 lesions are the white spots we see that do not necessarily have enhancement at this point in time, but must have at some point) in terms of number and volume, as well as loss of brain volume (atrophy).
New/newly enlarged T2 lesions (‘white spots’):
In TRANSFORMS, there was a 31% - 42% reduction on the mean lesion count as compared to IFNB-1a and in FREEDOMS it was 74% as compared to placebo.
Gadolinium enhancing (Gd+) lesions:
In TRANFORMS, after 12 months, there was a mean of 0.5 Gd+ lesions in the IFNB-1a arm vs. 0.2 in fingolimod 0.5 mg and 0.1 in fingolimod 1.25 mg.
In FREEDOMS, after 24 months, there was a mean of 1.1 Gd+ lesions in the placebo arm vs. 0.2 in both fingolimod arms.
Another way of looking at this, is that in TRANSFORMS, the percentage of patients free from Gd+ lesions was 80.8% on IFNB-1a, 90.1% on fingolimod 0.5 mg and 91.2% on fingolimod 1.25 mg. There was no statistical difference in the percentage of participants free from new/newly enlarged T2 lesions (45.&% vs. 54.8% vs. 48%). In FREEDOMS, 65.1% of participants on placebo were Gd+ free compared to 89.7% on fingolimod 0.5 mg and 89.8 on fingolimod 1.25 mg. There was also a statistical difference in the percentage of participants with new / newly enlarged T2 lesions – 21.2% in placebo vs. 50.5% in fingolimod 0.5 mg and 51.9% in fingolimod 1.25 mg.
Looking at the data together, it argues how similar TRANSFORMS and FREEDOMS were and it explains why there was no statistical difference in the percentage of participants with new / newly enlarged T2 lesions in the three arms of the TRANSFORMS trial: namely, because the IFNB-1a arm also had an almost 50% of participants with no new or newly enlarged T2 lesions (as compared to 21.2% in the placebo arm of FREEDOMS).
It is not surprising, then, that there was less change (accumulation) of T2 lesions from baseline in the fingolimod arms as compared to placebo (in FREEDOMS) and not as compared to IFNB-1a (in TRANSFORMS).
Not just accumulation, but loss
We are not only interested in T2 lesions, but in T1 hypointense lesions (unfortunately termed ‘black holes’) and brain volume.
In FREEDOMS, the mean change from baseline in T1 hypointense lesion volume was 50.7 in placebo vs.8.8 in fingolimod 0.5 mg and 12.2 in fingolimod 1.25 mg. In TRANSFORMS, there were only nonsignificant trends in favor of fingolimod over IFNB-1a.
In terms of brain volume, all of our brains lose volume (0.2-0.4% per year) over time (just as the rest of our body shrinks), but this can be accelerated in MS. One of our goals is to slow down any loss of brain volume. In TRANSFORMS, the percentage change in mean brain volume from baseline was -0.45 for placebo vs. -0.31 in fingolimod 0.5 mg and -0.3 in fingolimod 1.25. Probably since FREEDOMS was one year longer, the numbers are higher and the change for fingolimod 0.5 mg was -0.84; for fingolimod 1.25 mg it was -0.89 and for placebo it was -1.31. In FREEDOMS, fingolimod significantly reduced brain volume loss at 6, 12 and 24 months, compared to placebo.
Now, let’s move on to the elephant in the room: safety.
4. 4. Oral fingolimod (FTY720) in relapsing-remitting multiple sclerosis (RRMS): safety findings from TRANSFORMS and FREEDOMS trials.
When choosing a disease modifying agent with your neurologist, we usually consider efficacy (how strong it is), safety, tolerability, convenience and whether the medication will fit into your lifestyle (i.e. whether you will actually take it). The strongest medication in the world is of little use if it is not actually getting into the body.
When TRANSFORMS came out, many of us were concerned with the possibility of safety issues. We clearly have a drug that is effective (it beat one of our current injectables), but the question was the side effect profile. Then FREEDOMS came out and looked more promising. In this poster, we look at the combined safety information.
Firstly, overall less people discontinued the study who were on fingolimod 0.5 mg (8% in TRANSFORMS and 13% in FREEDOMS) than on fingolimod 1.25 mg (13% in TRANSFORMS and 23% in FREEDOMS), or the control arms (IFNB-1a in TRANSFORMS at 11% and placebo in FREEDOMS at 21%).
In clinical trials when you look at the percentage of people who have any adverse event (AE) it is always high, but the serious AEs (SAEs) are what concern are much more.
The overall incidence of AEs were similar for all the groups (91 – 94 %), except the TRANSFORMS fingolimod 0.5 mg where it was 86%.
AEs that led to discontinuation were more likely in the fingolimod 1.25 mg group (10% in TRANSFORMS and 14.2% in FREEDOMS). Of the IFNB-1a group in TRANSFORMS, 3.7% had any AE that led to discontinuation and in FREEDOMS the placebo arm had 7.7% while the fingolimod 0.5 mg arm had 7.5%. The reason for the higher percentages of those who discontinued in FREEDOMS as compared to TRANSFORMS was that it was one year longer.
Death:
In FREEDOMS, 2 participants died in the placebo arm.
In TRANSFORMS and FREEDOMS, 3 participants in the fingolimod 1.25 mg groups:
A. Disseminated varciella zoster virus infection (chickenpox all over the body)
B. Herpes simplex encephalitis (brain infection with herpes)
C. Suicide
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