V + O frontline approved by FDA

[avzuclav]

Thank you to all of those participating in clinical trials!

news.abbvie.com/news/press-...

[Justasheet1]

Wonderful news. I wonder if relapsed patients still get V+R or can they get the obinatuzimab?

Jeff

[AdrianUK in reply to Justasheet1]

It's fascinating to compare the license for Venetoclax in the UK linked on that press release that now simply says "for CLL/SLL" without any qualifications vs the one in Europe, which has yet to include this latest trial, and is much more specific only allowing the precise groups studied (note for example this latest study was actually only inclusive of patients who had a specific medical exclusion for FCR) and also insisting Venetoclax should be used as per the combinations used.

So it could well be that in the UK and EU if you use it firstline you would use it with O, second line with R, and third line or due to 17p deletion on its own which seems crazy really!

In the USA I get the feeling you are much more likely to have a freedom to mix and match the combinations and order of drugs, and not worry too much about whether a particular drug or combination has been studied in the exact same group of patients you are in.

This difference does seem a little crazy but the Brits and most europeans do tend to be sticklers for sticking to the licensed indications of products and following broadly the clinical trials as examples of what we are meant to do.

(See medicines.org.uk/emc/produc... )

The other critical question for ALL of us now is what is the best strategy for us to use in terms of sequencing medicines. There are two competing strategies now clearly right from the beginning of treatment.

We might start with either strategy and switch to the other but ultimately we are likely to need to choose one which fits our personality right as it seems to me it is now not clear what is the best approach:

A. Hit CLL hard and try to do our best to eradicate it, hopefully enjoy a long remission without taking any medicines (or just maybe a cure?!?)

In thus case we might decide to take venetoclax firstline (presumably with a CD20 antibody), or if that is not yet funded for us, FCR.

Some of us might see 20+ year remissions with such a strategy, and just possibly even a cure. Remember a small number of the early FCR patients have now got to more than 20 years relapse free which has to make you wonder if they are cured. It would seem likely Venetoclax in combo may do the same for at least some patients, and possibly better i.e. maybe even longer remissions, or a much higher proportion of patients getting these long remissions.

After enjoying our first treatment free remission, if and when we do relapse, we could still take venetoclax in combination with one of the two CD20 antibodies. Even in the UK every patient has this option as of right now and can choose between this and ibrutnib for second line treatment which will then be fully funded.

After our second treatment we would then hope for another equally long remission since time-limited treatment with a long break in between will hopefully not lead to treatment resistance for most of us (tho we don't know yet how often CLL will become venetoclax resistant).

Followers of this strategy might like the idea of fighting, destroying, nuking, wiping out their CLL and hoping for a cure.

It would seem that we could keep on this strategy for as long as we wanted to, or at least until venetoclax looked like it no longer was working efficiently. Perhaps for example if the length of the remissions were getting shorter. What if (and this is just an example estimate of course and in no way a promise of what the future will hold) we might see someone who had a 10 year remission on FCR then a 20 year on ventoclax, then a 15 year remission after retreating with venetoclax. Even a 40 year old with CLL would be pretty happy with that strategy if that was how it worked out provided it gave them a reasonably good quality of life in the meantime.

Then presumably only once venetoclax stopped working so well, the folowers of this strategy would presumably shift to the second strategy that some people will have decided instead to start with...

B. Accept that CLL is an incurable illness and so begin taking a long-term medicine to contain it and allow us to live better with it for as many years as our CLL remains sensitive to it (or we have side effects we can't tolerate).

This strategy is based on the excellent clinical data behind ibrutinib that has shown very high response rates, with great clinical and symptomatic improvement in many patients who take it, and high response rates, low relapse rates and high survival rates.

Amazingly ibrutinib does all this whilst almost never causing MRD negativity or in other words getting close to eradicating the CLL.

One might think of this as a more gentle approach, kind of like coming to terms with your CLL and living with it better, all the while making the environment for CLL in your body MUCH more hostile so initially it is just pushed out of its comfortable home, even increasing the numbers in the blood, but then it does actually gradually get killed off, just not usually in such a dramatic way as under the first strategy.

This approach may suit people who dont want to be quite so aggressive in their treatment choice, although to be fair it is not at all clear that Ibrutinib is much better tolerated in the typical patient than venetoclax as they are both generally quite well tolerated really (although of course in some patients each of them can still sometimes have quite severe side effects).

Of course there would be nothing stopping you starting with this approach and then moving on to the 1st strategy perhaps by adding venetcolax to Ibrutinib if that becomes a widespread and licensed approach once the V+I studies complete.

Which will it be then?

If I was the makers of ibrutinib I would be a bit worried right now, as if people decided on mass they wanted the first strategy it would dramatically reduce the amount of ibrunib used. Heck even if the only big change was it becoming mainstream to add venetoclax to patients on Ibrutinib with the goal of getting them to MRD negativity and off all medicines for a while, that would be a lot less Ibrutinib being used than if every year a new group of patients start Ibrutinib and then simply keep taking it year after year until it either stops working or they have side effects they cant bear.

We dont have the data to usefully make a rational choice between these two strategic viewpoints. And nobody is going to make a large enough trial to help us for second line decisions so we may have to simply make the plunge and keep an eye on FLAIR data as it is released over time (since FCR vs I vs VI will give an idea of what is doing best tho again we would have to wait 20 years to really know, and one question will be which strategy do FLAIR participants do second time round when they need retreating? I wonder if they might want to add an extension for the FCR group to re-randomise them when they need another treatment rather than as at the moment we drop out of the treatment portion of the study onto standard of care at that point ...tho still followed up for outcomes for life).

Key questions will be

--- which strategic approach (A or B) makes us live longer?

---which is associated with better quality of life in terms of side effect burden during treatment and also over the years (e.g. what if V+R is a bit harder to take initially but leaves people feeling better once they stopped it than those still taking ibrutinib?)

---Specifically which approach will best minimise FATIGUE? Surely that is a critical question nobody seems able to answer?

----Also, and this will likely directly impact on the first question, which approach leads to the best functioning of our immune system (here we have some evidence that all treatments initially worsen immunity, but some limited evidence that perhaps ibrutinib in the long term actually IMPROVES immunity, so not at all clear whether being treatment free for years on end or on an ongoing treatment will be best from this perspective.

What do you all think?

When you need that next (or first) treatment will you be heading straight to the Venetoclax queue (with or without a CD20 antibody) or will you be reaching for the ibrutinib?

What of those of you already on long term Ibrutinib, if someone at some stage said you were now allowed to add venetoclax to it and could work towards hopefully stopping all medicines would you?

[Hidden in reply to AdrianUK]

Abbvie who makes venclexta also makes Imbruvica. i;m waiting for the imbruvica/venclexta front line approval.

[AdrianUK in reply to Hidden]

True...but CLL patients being on your product for a year then not for many years is less lucrative than those same patients being on your product for a decade or more (Even if they end up on BOTH your products for that year). I guess this is an example of a company being willing to cannibalise their own market for a better future for patients. Ultimately I suppose if EVERY person with CLL gets at least one of their products each time they relapse this will be just fine for the company financially.

[Hidden in reply to AdrianUK]

but thats the way the drug business goes. In many cases-not all-a newer improved different drug come along and the old one goes bye-bye.

[AdrianUK in reply to Hidden]

Maybe a company should be required to divest one of the drugs if both are market leaders in the same indication since then a true competition would ensue....mind you Ibrutnib is listed as being a Jaansen drug in Europe, so maybe that involvement is partly with a view to ensuring that an outside company makes sure that Ibrutinib is also given the attention it needs. What a great problem to have though having two such amazing drugs on your portfolio. No wonder lots of other companies are busy trying to create related drugs that share a similar mode of action to one or other drug and which hopefully are better tolerated. I wonder who will be the first to try and combine to molecules into one to make the single molecule have both effects (like Bendamustine is supposed to combine the mode of action of Fludabarine and Cyclophsphomade, though doesn't actually work as well sadly)

[Hidden in reply to AdrianUK]

abbvie owns several drug companies that own rights to multiple drugs. they license Jaansen-which is owned by Johnson and Johnson to do the marketing of Imbruvica.

[AdrianUK in reply to Hidden]

That makes a lot of sense. I must say I have worked with a lot of Pharma companies in my previous life, and whatever you may think of the economics involved most people who work in the companies want nothing more than to feel they have made a huge impact on the health and well being of patients.

Perhaps the industry isn't ideal in the way it is regulated. But it is one of the most tightly regulated industries in the world, and as such everything from the renewed interest in rare disease in recent years to the high prices seem are ALL direct consequences of the way the industry is regulated. We could make a lot of changes to improve the industry by changing the regulatory rules and structures.

But now we are getting off the topic slightly. Money may drive the pharma companies but that money is delivering lots of new drugs for us...so much so that we are almost spoilt for choice now.

And it is only going to get more like this. The first antidepressants and antipsychotics revolutionised psychiatry, successive waves of innovation improved on them leading to better side effect profiles and in some cases better efficacy.

Looks like we really are in for a serious boom in our choices in years to come....another reason to hold off on treatment for as long as you can to then be in the best position to choose a good drug (the longer drugs are on the market the more we know about them of course too)

[Jonquiljo in reply to AdrianUK]

I worked in the biotech industry for a number of years in prehistoric times. What I generally learned was that money is the driving force for all. They talk a good game about helping people, but everyone is first and foremost looking to score financially. That - i guess - is human nature.

We have a lot of other factors at play which will decide where to take these drugs (and subsequent drugs) in the future. If the costs become too prohibitive - at least in the US, the federal government which ends up paying about 50% of all of them - will jump in and get angry. This will just make a stronger case for strong price controls on these companies - and their greed just boxes themselves into a corner.

Then these pharmaceutical companies have their research staffs to worry about. If you keep someone working on a single drug (like ibrutinib) for more than several years, you will lose them to another company. A big problem among higher end research personnel is that they don’t want to be bored. They want to be rich and scientifically challenged. Usually a reward for success on one project (drug, etc) is to be transferred to something totally new and innovative. If places like Abbvie bore their scientific staff then they eventually lose their advantages over others.

CLL is a good “model” cancer to work with. It likely is not as big a revenue producer than treatments for more common cancers. But just like good in vitro systems make it much easier to develop pharmaceuticals for real life (in vivo) uses, good model drugs give a sound scientific basis to move to applying things learned to other systems, diseases, drugs, etc. In a nutshell, treatments for CLL probably set the stage for cures for other diseases. That is very profitable!

So pharmaceutical companies face many things when looking at drug strategies. Immediate payoff and cash flow is only one of them. They have governmental regulation and their own internal corporate needs to consider. Right now these companies are probably worrying about where they will be and what their profits will be in 2040, not 2020. This likely is good for cll patients. If they shut us out with ridiculous treatment strategies or outrageous prices - they lose in the future (not just us!). Apple computer is a good example of a company that got greedy and failed to look adequately toward the future. They now have a limited bag of tricks - and can overcharge just so much on yesterday’s technology. The same is true in the pharmaceutical industry - perhaps more so.

So the jury is still out on where this will go.

[AdrianUK in reply to Jonquiljo]

The pharmaceutical industry works on a model of capitalism, surprise surprise. Basically capitalism takes human greed and turns it around for the good of all. If someone makes a product we all like and buy then they get rich. If we hate it and dont buy it they dont!

BUT the pharma industry is NOT a free market. It is highly regulated and controlled by rules and incentives. So there are quite generous and important incentives (essentially subsidies) for companies to make drugs for rare diseases like CLL.

Before those incentives nobody made drugs for rare diseases because the common diseases have more patients so you can make more money. With a rare disease you will always be at risk of making less money hence the need to have these incentives on the regulatory side which I won't bore you with the specifics of.

Having said that despite the incentives a rare disease means by simple maths that the price will have to be higher. If you will only ever be able to sell thousands or tens of thousands of patients your drug then you will need to charge each patient considerably more than if you could sell millions of patients your drug!

Now there are some benefits to rare diseases where they do allow you to scale back your development slightly. But those scaling backs doesn't mean that the costs are say a thousandth of a drug for a common disease. So the rare premium still needs to apply.

One final point is that obviously countries like the UK which regulates drug prices both at the point of listing them for sale, and at the point of deciding whether they will be funded or not by our single payer (often involving a secret price discount given by the company to the NHS) then invariably we pay less than the USA in which companies can essentially charge whatever they like!

[Jonquiljo in reply to AdrianUK]

The lucky part for the pharmaceutical companies is that they take one drug and adapt it for use in many diseases. How many diseases is Ibrutinib used for? Many!

I really leaned back years ago how much money and more money meant to these people.

These people may get major financial incentives to produce drugs for rare diseases, but they take full advantage at all ends. And, of course, our country (USA) is so pathetically corrupt that we allow these companies to charge whatever they’d like.

[AdrianUK in reply to Jonquiljo]

And thanks to how generous you are you do tend to get the drugs released to you first. Then they can say to the Europeans “but the Americans pay for it....” and we can feel smug about the fact that we negotiate a MYCH cheaper price!

By definition when there is a really innovative and unique drug there is no competition. 101 of capitalism is you have to regulate it to make sure that the public isn’t screwed over by monopolies. In this case for example if venetoclax had been produced by a different company they could have priced it lower than ibrutinib and made a huge deal about how you don’t need to be on it for life and do sell it against ibrutinib. What’s more likely is they will go for the combination tho I’m

Not sure if there’s any ongoing study that will lead to an actual license for that.

[AllanJardin in reply to AdrianUK]

Hi Adrian. I have worked for multinational pharmaceutical companies in Latin America for more than 3 decades and obviously they all put profits as their high priority even dropping some new drug development projects if they are not financially viable. On the other hand, thanks to some good R&D projects we are now able to have new drugs such as V and I. Coming back to your original point, I am much more in favor of the alternative A for suitable patients. In this sense, in my case I remain untreated but thinking seriously about taking V+O as initial treatement, since it would provide a relative long remission with perhaps less side effects than FCR. Regards, Alan

[AdrianUK in reply to AllanJardin]

I think it is very interesting indeed that this new data has lead to the FDA granting Venetoclax what seems to be an indication for treating anyone with CLL.

The fact that this particular study was not open to all comers makes me think it is unlikely that the EU/UK will follow suit as we are much more likely to limit it to the specific group of patients (i.e. those not suitable for FCR). I hope I am wrong, though. For sure I find it hard to imagine that NICE will approve V+O as a first line option for everyone at this point.

I wonder if we will see V+O rapidly become the leading initial treatment since it would hopefully lead to people being able to stop and enjoy a long remission, then potentially re-use it. Then Ibrutinib presumably would be reserved for Venetoclax failures. In which case the glory days of ibrutnib will rapidly be behind it.

Which then leads to the thought, if people are on ibrutnib now and doing well, at what point do doctors start switching them to Venetoclax to try to get them to a treatment free status?

Could it be that ibrutnib which for the last few years has been on the ascendency will actually rapidly be replaced by Venetoclax as the drug of choice?

Ideally we could do with a head to head study between Venetoclax and Ibrutinib but I don't see anyone being able to fund that, so we are in a bit of a quandary. How will we and our doctors make a call between these two medicines in the future I wonder?

Here is the information that shows how the FDA has interpreted this as a license for anyone with CLL to use Venetoclax:

CURRENT PRESCIBING INFO (see rxabbvie.com/pdf/venclexta....

VENCLEXTA is a BCL-2 inhibitor indicated:

• For the treatment of adult patients with chronic lymphocytic leukemia

(CLL) or small lymphocytic lymphoma (SLL). (1.1)

• In combination with azacitidine or decitabine or low-dose cytarabine for the

treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

This indication is approved under accelerated approval based on response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.2)

OLD USA PRESCRIBING INFO (when it was not yet first line see accessdata.fda.gov/drugsatf...

INDICATIONS AND USAGE

VENCLEXTA is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. (1)

[AllanJardin in reply to AdrianUK]

Hi Adrian. Thank you very much for the further analysis on the subject. Many points will be cleared with additional research and will take some time to be concluded. Regards, Alan