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Hello, this is Dr. Marc Cohen, Emeritus Professor of Medicine at the Mayo

Clinic and Clinical Professor of Medicine at the University of Colorado

Medical Center. I’m happy to be with you participating in Cleveland Clinic’s

Rheumatology Highlights Report and I have the privilege of presenting the

New Agents and Small Molecules in the Treatment of Rheumatoid Arthritis.

This section is particularly interesting, and I have some thoughts to share

with you

I have nothing to disclose.

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I am actually going to talk about a number of new agents, almost all

biologics. I have them listed here we’ll probably spend the most time on the

Janus Kinase inhibitors. This certainly attracted the most attention when this

information was presented.

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So, first I’d like to talk about Tofacitinib. It turns out a week before (slide 4)

the ACR meeting; the FDA approved Tofacitinib with some limited

indications. This drug is a JAK 3 inhibitor, it may inhibit other JAKs as well

but primarily a JAK 3 inhibitor with now a large body of trials in patients with

rheumatoid arthritis. We will refer several times to the five phase 2 and 3

trials, some of which have long term extensions. So, this is quite a large

number of patients, 4,789 patients, but with limited patient years of exposure

as you might expect as this product is new. The first study looks at

Tofacitinib and the risk of herpes zoster; this was presented by Winthrop et

al, again looking at the phase 2, 3 and long term extension trial. They found

no dissemination or deaths from zoster, 90 cases in the phase 3 trials with

an incident rate of 4.4. Note that the placebo rate was 1.5, and in the long

term extension the incident rate was 4.5. So, it is clear that RA patients

treated with Tofacitinib have higher herpes zoster rates than those reported

with other biologics. So, something to be careful about I think. Not that many

cases, but perhaps another thing to think about with this new product

Tofacitinib.

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Next, is again a safety review by Geier et al (slide 5) who does work for

Pfizer. And, this was a meta analysis of malignancies, serious infections, and

serious adverse events with Tofacitinib compared to other biologic

treatments in RA clinical trials. So, a very large meta analysis, 80 a

randomized clinical trials with 31,000 patients vs. the Tofacitinib, five phase 3

control trials and long term extensions. Event rates for Tofacitinib with

regards to malignancy, 0.62, with regards to serious infection, 2.91 and with

regard to serious adverse events 10.3. Interesting, I think that this is about

the same as what has been reported across all the other biologics. This

again is in a relatively small number of patients with a relatively small

exposure. So, this is early days with regards to this drug. But, an interesting

approach if you like meta analyses and those of you who heard me before

know that I don’t.

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The last of safety slides (slide 6) looks at TB and Tofacitinib. Again presented

by Winthrop et al, again looking at that collection of phase 2, 3 and long term

extension trials, the TB incident rate was relatively small at 0.173 and varied

accordingly to where the patients were from. High areas of TB obviously

related to high numbers of patients treated with this drug. So, the RA

patients treated with Tofacitinib seem to have similar TB rates as other

biologic and even non biologic DMARDS. They do conclude, I would remind

you, that patients should be screened before this treatment, that there was

also some data regarding whether or not patients with latent TB infection

could be successfully and safely treated with INH while receiving Tofacitinib.

And, although there were a small number of patients, 209, the conclusion

was this was probably safe.

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All right. Now, moving on to other effects, remember that the clinical trials,

the five phase 3 clinical trials were out there. We are looking then for what’s

new, and one of the things that was new is the more careful presentation of

radiographic data. So, Desiree Van Der Heijde et al did present some

information regarding Tofacitinib from one of the phase 3 trials. This was the

trial of Methotrexate incomplete responders, originally 797 patients, 535 who

made it through 24 weeks. The efficacy was nicely maintained over the two

years with ACR 20, 50, 70 rates of 73, 48, 49, and 27. I think the nice

numbers, deaths, remissions also are fairly significant. And then, they looked

at mean sharp score changes. I want to be very careful that I remark here

appropriately because what they demonstrated was that the mean sharp

score change was 0.48 for the group that was 5mg BID, 0.23 for the group

that was at 10mg BID. They also had groups that had started on placebo

and then changed to 5mg of Tofacitinib BID and placebo changing ten. And,

my reading of the conclusion is that only at the 10mg BID dose was the

radiographic change data statistically significant. So, at 24 months with the

approved dose of 5mg BID, radiographic suppression was not obvious. So,

my conclusion is in Methotrexate incomplete responders, rheumatoid arthritis

patients treated with Tofacitinib, they can maintain efficacy through 24

months with inhibition of structural change only significant at the higher dose.

This does not mean some patients on the low dose did not respond, but

statistical differences were only seen at the higher dose.

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And, interestingly that paper was not the oral presentation. The oral

presentation was by Fleischmann et al looking again at efficacy and

radiographic effects this time in the Methotrexate naïve study. The last one

was Methotrexate incomplete responder this is Methotrexate naïve who were

given either Tofacitinib 5 BID, 10BID or compared to Methotrexate

maintained, the drug was better than Methotrexate as monotherapy over 24

months. DAS remissions were higher on Tofacitinib. Mean sharp score

changes were better, actually smaller and statistically significantly smaller on

Tofacitinib. So, here as monotherapy, Methotrexate naïve patients treated

with Tofacitinib they improved signs and symptoms, physical function, and

inhibition of structural change vs. Methotrexate monotherapy. Interesting

about the two groups, interesting which was presented orally, a very

interesting and please read this data carefully

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Then, other studies looking Tofacitinib, certain aspects of it. There was a

very nice small paper from Southern California, on effects on cholesterol and

lipids, demonstrating that the decreased levels that we see with high disease

were normalized on Tofacitinib. That was nicely done, although there were

only 36 patients treated with a higher dose. The next was response

particularly with regards to achieving low disease activity. Tofacitinib vs.

Adalimumab, this was from Van Vollenhoven et al, a nice presentation

looking at several doses. But, this was post hoc and really concluded that if

you didn’t respond by three months with achieving low disease activity you

might not ever get there. So, I think interesting conclusion and I would be

careful about thinking that Tofacitinib was superior to Adalimumab. Effects on

patient reported outcomes from Burmester and the German group et al

demonstrating that Tofacitinib was able to achieve statistically significant

improvements in multiple patient reported outcomes.

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There was a small trial of patients on this drug for up to 48 months , so now

up to 6,000+ patient years of exposure, again demonstrating relatively stable

responses and no new safety signals, but again a small number of patients

and still not exposed for very long. We’ll have to continue to watch this. And

then, lastly a paper by Van der Heijde et al that I did not particularly care for

which looked at the effects and radiographic progression in the trial called

the Scan trial, but this was a post hoc look at those patients you might think

were most likely to radiographically progress. CCP positive, CCP RF

positive, very high disease burden, baseline erosions. In those patients, both

the 5mg BID and 10mg BID dose of Tofacitinib demonstrated statistically

significant inhibition of damage progression compared to placebo. Hopefully,

these drugs would be better than placebo. So, they post hoc picked the

patients most likely to progress and demonstrated the drug did work

compared to placebo in that group. So, we have Tofacitinib now approved,

this is very new data regarding particular radiographic effects they did not

ask for or get from the FDA radiographic inhibition approval and we’ll see

where they want to take this drug next with regards to clinical studies.

There’s some updated information about this drug that is now available.

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Then, quickly now another JAK inhibitor, this time a JAK 1/2 inhibitor called

Baricitinib looked at in 24 week studies first by Genovese et al. 301 patients,

Methotrexate incomplete responders demonstrated that the drug works

clinically, it worked for suppressing disease activity and HAQ with a

reasonably, reasonable safety profiles without. So, with reasonable safety

profiles without much change compared to prior biologics.

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In fact, there was a substudy in the next abstract by Peterfy et al looking at

MRI change, and in fact MRI changes were also suppressed by this JAK 1

JAK 2 inhibitor Baricitinib. So, I think this drug is also going to go forward, no

new safety signals and two nice presentations regarding its effects.

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Next, and quickly another JAK 1 inhibitor so you get the feeling that JAK

inhibition is popular and perhaps important. This is a very small study of 24

patients suggesting that selective JAK 1 inhibition might be efficacious and

safe. That drug does not have any other JAK inhibition besides 1

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and interesting paper from Kass et al regarding a gonadotropin releasing

hormone antagonist in rheumatoid arthritis. 99 patients treated with

Cetrorelix, this is an antagonist to gonadotropin releasing hormone which

has been found to stimulate immune response. So, you’re blocking that

stimulation and in fact the drug worked quickly to improve symptoms in

rheumatoid arthritis patients. It may be doing it via lowering TNF levels. So,

this is a very interesting paper, nicely presented in an oral presentation about

a new way of looking at perhaps TNF suppression or at least improving

some patient signs and symptoms with rheumatoid arthritis.

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Next and from this point forward some very small studies (slide 15) about

novel approaches. Ozoralizumab, which is a drug which is a very specific

small, what is called a nanobody which neutralizes TNF and binds to other

proteins. So, this is one of those very small, very engineered, very focused

antibody this one blocking TNF. Fair number of patients, 266 eventually

treated, two year data, so fairly impressive presentation by Fleischman et al

demonstrating that this nanobody was effective and very well tolerated in

Methotrexate incomplete responding rheumatoid arthritis patients. So, this

possibly will go forward as well.

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Other approaches are summarized now quickly this F8 IL 10 product, very

interesting way to get at anti inflammatory sites with IL 10, but only three

patients treated, so a nice concept if you will, a nanobody to the IL 6 receptor

was reported. This time in 28 patients. There is more work on anti IL 6

monoclonals; this is Olokizumab which blocks the final assembly of the IL 6

signaling complex, so different than usual. 38 patients treated with some

efficacy so a very interesting and novel approach, perhaps going forward.

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And then, lastly the novel JAK inhibitor which blocks JAK 1 and 3, so an

interesting combination. Really, phase 1 / 2 trial given to patients who were

already on Methotrexate, no unusual toxicity and phase 2 trials upcoming.

And then lastly IL 21 which is this cytokine that comes from or is excreted by

certain cells and thought to participate in rheumatoid arthritis ongoing activity

if you will. So, it’s produced mainly by activated T cells especially T17 cells,

and in this trial, little trial 64 patients, it seemed to work in its highest dose.

Now, whether or not this will work in longer term trials, whether or not they

can get the right dose and whether or not it will be safe remains to be seen.

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But, what I’ve tried to do is present the most data about Tofacitinib because

that product is now available. And, approval is very close to the presentation

of the data that I’ve shown you. Baricitinib, another JAK inhibitor, this time 1 /

2, probably going forward. Specific JAK 1 inhibitor also available, a novel

JAK 1 / 3 inhibitor coming down the road, and some other novel approaches

to the treatment of rheumatoid arthritis, really indicating that our future

should be bright; we’re using a lot of new approaches. The JAK inhibitors

particularly fascinating in that they seem to continue to work over long

periods of time, at least longer periods of time without any readjustment from

the immune system and without any new toxicities, but time will tell.

So, very interesting data, a pleasure to be with you, love to talk to you about

these things if you want to find me, and I certainly look forward to talking to

you again in the future. Thanks so much for listening, and be sure to listen to

the other presentations by other presenters. Thanks so much.

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