Alternatives to Ibrutinib ???: Here is an... - CLL Support

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Alternatives to Ibrutinib ???


Here is an interesting article about the expanding field of BTK inhibitors that are in the pipeline. Some look very promising as superior alternatives to ibrutinib. This is good news. Even more good news is that they offer potential price competition for ibrutinib.

This also raises the question about how will all of these companies be able to recruit enough trial subjects in order to fill these trials? This is a big market with significant financial opportunity. Plus all of these drugs have limited patent protection lifetimes. This means that there will be big pressure to get these trials staffed and completed as soon as possible. The early birds will get the worm!

35 Replies


Excellent article. I’ve been waiting for an article like this.


I agree. This is an excellent article both for the information about alternatives to ibrutinib as well as for explaining the distinction between covalent and non-covalent inhibitor binding. The figure showing the binding of ibrutinib to BTK, and the known hot spots that can lead to ibrutinib resistance is beautiful.

Thank you for your post.

The one that I am really excited about is SNS-062 by Sunesis located in South San Francisco. This one looks very promising and my new hematologist is extremely excited about it.

Prior to 6 months ago this is the only type of article I read about drugs. That is from the perspective of a stock investor. Now I read from the patient perspective seemingly almost everyday. The takeaway here is that the cost of these drugs are so expensive not only because of the massive upfront costs for research and development, testing, etc. but because there is always another company waiting in the wings trying to invent a better mouse trap and make your product obsolete. It is hard to fathom that the darling drug Ibrutinib could become passé but that is what this article suggests. Thank God for capitalism and the profit motive. It will add years to many of our lives.

It's interesting that one of the new BTK inhibitors, Acalabrutinib / Calquence, is $14k / month vs IB at $11k / month. They're certainly not trying to compete on price!

CllcanadaTop Poster CURE Hero in reply to bhayes84

There is no competition in CLL drugs... price or in any other way.. especially under the Orphan Drug Act, all there are is government perks... extended patent protection, tax rollbacks, almost closed market etc...


AdrianUK in reply to Cllcanada

Before the orphan drug act and similar things in Europe there wasn’t much incentive for companies to produce drugs for rarer disease. The system isn’t perfect but it is making companies want to develop drugs for conditions like this and even rarer ones. There is a simple maths issue which is that it doesn’t cost a thousandth of the price to develop a drug that is only a for a thousandanth of the number of people.

One interesting factor is that drugs always cost more in the USA than Europe which I believe is to do with us having cost effectiveness bodies and socialized medicine vs insurance companies which end up with an inflated cost for everything.

Indolent in reply to Cllcanada

I suspect that we will eventually see competition in two places as a result of the expanding number of compounds in the pipeline..

First, there will be competition to find patients willing to go through clinical trials. With all of the new drugs and potential combinations, there will be an increased demand to find willing and viable candidates. And since they all face expiration dates on their patents, it will be important to get the trials done as quickly as possible in order to reap any benefit from that patent protection. At present, less than 5% of patients are willing to undergo the rigors of trials. It looks like a limited supply of patients running against a rising demand for clinical trials. Something has got to give!

Second, when these drugs eventually do enter the market you will again have a supply versus demand issue. The patients will have more options. And the market size is not going to grow without bounds. We have roughly 20,000 new cases of CLL each year in the US. This will not rise drastically. So supply of drug options increases will enter a relatively stable potential market. Something has got to give!

So that is my prediction. Despite all of the abusive rules that favor the drug companies, market forces will eventually come to bear. The timing is uncertain, but the result is unavoidable.

AussieNeilAdministrator in reply to Indolent

I think you'll find it worthwhile reading about the development of the first successful monoclonal antibody for another leukaemia - CML: It took some convincing to fund the approval process for Imatinib/Gleevec, due to considerably to the small perceived market for the drug. However, the drug was so successful, what was initially a fairly stable market grew quite considerably, because patients who were living limited lives, went to having a normal life expectancy for which they depended on Imatinib/Gleevec maintenance therapy. I can recommend reading about this in more detail in the book "Emperor of all Maladies".

Extending that success to CLL is financially not long term sustainable, but thankfully we have CLL researchers that are actively exploring combination therapies that can give us long remissions and perhaps even a cure from a limited time treatment.

bhayes84 in reply to AussieNeil

I haven't read "Emperor of all Maladies" but the PBS series based on it was very good. Unfortunately it doesn't seem to be available on the PBS website.

After digging I see the 3 part series is available on Amazon: free under Prime, $6 per part otherwise.

Jonquiljo in reply to Indolent

There are a lot of things that you aren't taking into account.

1.) BTK inhibitors are useful for a number of cancers.

2.) Some 2nd or 3rd generation BTK inhibitors will not be better than others.

3.) There is a world wide market for these drugs if the prices lower a bit. The US system is an anomaly. Medicare and Medicaid are big markets for these drugs - but they aren't allowed to negotiate prices when paying for these meds. So, for example, if your co-pay for a year's supply of Ibrutinib is $9,000 - the US government picks up the tab for the difference from retail - of $14,000 a month - ~$170,000 per year. The private insurers probably pay half retail for their insureds - but that is likely a small fraction of patients. Either way their hideous pricing will eventually anger the hands that feed them. They already are.

4.) As the price goes up, there will be a lot more people willing to go through clinical trials. Many people cannot even pay the co-pay for the meds themselves and the assistance agencies are constantly running our of money as the meds become more expensive.

Actually the "abusive" rules that favor the drug companies will make it easier for "us" to actually get these drugs cheaper. And yes, with a bit of competition out there they will start to fight against each other. If they don't lower prices, consumer sentiment will force pharmaceutical reform in the US. That will lower prices all over the world.

And, of course, there is the US Medicare and Medicaid systems that are sitting there paying full price for all drugs, spending trillions of dollars and running quickly out of money because of it. I suspect that organizations like the UK's NHS are at a disadvantage as they are competing with a market (USA) that will pay these people list prices. Ego, is also a large factor - as aside from money, these companies want to think they are better than each other.

Scientific study that likely began 30 years ago is now paying off for these people. They are in a feeding frenzy right now, but it will be over in a relatively short time. They knew this 30 years ago and want to extend it as long as possible.

We are just in a new phase of cancer treatment where a lot of treatments are oral drugs, not infusion-based chemotherapy. The prices are not sustainable. Leukemias and lymphomas (especially the CHRONIC ones like CLL) are big targets for these companies. CLL is one of the biggest candidates. So yes, there will be a lot to see in the next 5-10 years. Even if the goal of MRD is eventually replaced by "cure", we still are going to be well supplied for a long time. It's kind of paradoxical that a "cure" for CLL will be the one thing that could push away the pharma companies. Instead of the potential of selling a patient 10 or more years of drugs, the prospect of only 3 months to cure him/her is not so appealing from their point of view.

HopeME in reply to Cllcanada

Chris: What is driving the development of these drugs for CLL? It seems like there are many drugs coming to market. Are you suggesting the development of these new CLL drugs being driven by incentives created under the Orphan Drug Act? Is Ibrutinib a drug that was developed under the act? Who pays for the sunk development costs if Ibrutinib is replaced? My assumption is there must be a profit motive given the wave of medicine coming to market. I’d like to understand this more.

Thank you

CllcanadaTop Poster CURE Hero in reply to HopeME

Most drugs come from start ups, and they need ODA to even get it to the lab stage. Most hope to be gobbled up by a big player... like Pharmacyclics was...for Imbruvica (ibrutinib)...Acerta for acalabrutinib, ONO/Gilead for tirabrutinib

Jonquiljo in reply to Cllcanada

Chris, I'm not sure where to check it but I will look around. If the ODA (Orphan Drug Act) applies here - it written (in your link) that the drug must be intended to treat diseases with less than 200,00 patients in the USA. We get 21,000 new cases with CLL a year in the US, which must make the total number of US CLL patients much higher than 200,000. Also, I don't know how it would work, but the approvals for Ibrutinib (as an example) are multiple - it is approved for multiple diseases.

I guess I am making a silly point anyway as the drug companies are coming up with such novel "cures and treatments" that they charge as much as the market will bear. I know there are some out there retailing far in excess of $500K per year!

I guess I am saying that all the tax breaks, etc. for any cancer drug possible - don't really help the profit motive. When you can charge whatever you want - and these companies do literally that - you have all the incentive in the world. Plus, now (in 2018) that the top US corporate tax rate has gone from 35% to a flat 21%. That alone generates billions of dollars of additional cash flow (income) for most pharmaceutical companies. This is a lower rate than most individuals earning over $40,000 a year. There are other perks that are not worth getting into. The bottom line is that any US based pharma company has all of the incentive it needs.

CllcanadaTop Poster CURE Hero in reply to Jonquiljo

No CLL is under 200,000 it is also a Rare and Neglected Disease... Each indication is treated separately so MCL, CLL and WM are all under the act... as separate diseases...

General figures

US Epidemiology: 2016

Incidence: ~19,000/year

US Prevalence: ~130,000 cases

• Median age at diagnosis: 71 years

Jonquiljo in reply to Cllcanada

Oh, well I guess I would have expected more people with CLL than that. I keep forgetting that CLL is somewhat uncommon.

Either way, I doubt that the tax incentives and the giveaways are useful now. The new US corporate tax scheme for 2018, while horrifically wrong, does give most corporations an enormous amount of cash to play with that they never had before.

But the relaxed regulations for clinical trials and overall testing from the orphan drug act probably makes it a lot easier for all these new drugs to make it to the market.

Ladydi49 in reply to bhayes84

How do people afford these drugs?

bhayes84 in reply to Ladydi49

Most are on Medicare which picks of 95% of the cost and I would guess most people have the copay covered by assistance programs. AstraZenica which makes Calquence (brand name for alcalbrutinib) has their own assistance program.

Indolent in reply to bhayes84

Even with Medicare, most are faced with $10K or more each year..... every year. That's a big hit to most budgets. And even more insidious, these exorbitantly expensive drugs is putting a huge drain on this insurance program, which is already on an unsustainable path. All of this is like watching a slow motion train wreck unfold.

bhayes84 in reply to Indolent

I would guess many/most patients are getting assistance with copays. When I got assistance for Ibrutinib my doctor said all of his patients, except the very wealthy, have been able to get assistance. I'm keeping my fingers crossed that I get assistance for acalabrutinib - I couldn't afford the full copay.

I agree about these costly drugs having a huge impact on Medicare; especially as the population gets older.


I had many ARs with ibrutinib so my Dr switched me to a second generation BTK acalabrutinib- 100mgtwiceva day.? it is great no AEs at all for me. It has a 41% PR and 40% CR. Making overall response 81%!!! Not bad.

I now have full CR with minimal residual disease (MDR).

Justasheet1 in reply to Hidden


I’m glad that you were able to have great results from the acalabrutinib.

I hope that this drug is approved for CLL soon.

I hope the fact that you have a different disease does not confuse others on this site.


bhayes84 in reply to Justasheet1

Jeff, many doctors, including mine, prescribe it 'off label' for CLL and Medicare still covers it.


Justasheet1 in reply to bhayes84


I’m really surprised to hear that they would pay for it. It’s never been my experience. I’m extremely pleased for you.


bhayes84 in reply to Justasheet1

My understanding is that it was just recently added to the Medicare Part D drug list. I'll be happy if I can get copay assistance. Before it was added to Part D AstraZenica was providing it at zero cost, so we'll have to see if the change is an improvement for me.

Meanwhile, on a personal note, two months after stopping Ibrutinib I'm still having episodes of awful blistering rashes with no idea how long they will continue.

Justasheet1 in reply to bhayes84

Do they feel it’s still due to the Ibrutinib? Or is it the acalabrutinib? Maybe BTK inhibitors aren’t your thing?

Venetoclax headed your way?

bhayes84 in reply to Justasheet1

I haven't started acalabrutinib yet so we're assuming it's due to IB, though my onc has only seen one slightly similar case. I've done lots of Googling and can't find more info. Frankly I don't know where to go to figure this out.

Interestingly the acala was approved by my pharmacy and the first month billed to Medicare noting my copay is $754 (though it doesn't say I owe that yet). I hope to hear from AstraZenica this week.

Justasheet1 in reply to bhayes84

$754 a month? 🤯

bhayes84 in reply to Justasheet1

Yes. Breath taking isn't it? That's the 5% Part D copay of $14,333 for one month of acalabrutinib.

Ladydi49 in reply to Hidden

No cardiac issues ie high blood pressure, racing heart/A-fib, heart failure?

Part of me likes this article, it is fascinating all the chemistry, and I'm glad I read it! Also it opens up a window of understanding to what is driving research, since CLL is the most common blood cancer, they see more potential profit from developing drugs for it. Does that make us lucky? Hmm. I know that use of newer drugs is based on the trial results now trickling in. Regarding the next generation BTK inhibitors, might the competition between companies produce mistakes? Hopefully not. When I will need treatment, will I be offered a clinical trial for one of the new ones? Will I feel like a guinea pig, hoping not to get the wrong thing?

My questions are all rhetorical of course...

CllcanadaTop Poster CURE Hero

I'm sure in a few years ibrutinib will be sitting on a shelf and we will be on to the nexr 'great advance'. This has happened a number of times in CLL. Some of these new drugs won't ever see a market.

The path to a cure lies at the moment in combinations I think, but then you get companies who don't play well together, so the trend seems to get or buy the rights to many different types of treatments, with an eye to combination.

TGR is a case in point they have an ibrutinib like drug a Zydelig (idelalisib) like drug and a Gazyva like drug... all in their pipeline.

Gilead is doing the same... amassing new therapies, so all parts of a combination treatment will have Gilead on the label.

And speaking of Zydelig (idelalisib), I hear very little mention of it... I guess the blackbox warnings scare the average oncologist. However, for me it has been a superb treatment with few side effects, a far cry from the Imbruvica (ibrutinib) which was simply awful, in my case.

But, then again, I have friends who had great trouble with Zydelig (idelalisib), so you will never know until you try it...

I'm sure as the new drugs enter the market, it will be similar...some patients will do well on a particular drug, and others won't. This seems to be the nature of CLL treatment due to its very broad heterogeneity.

One size does not fot all, not now and probably not into the furure.


Ah, so the Master has finally spoken. Combinations 🤔

I go back and forth. I hate to burn through several drugs if it doesn’t do the trick.

I’m gonna be in some clinical trial when that day comes, so I guess if that’s the road research is going then I’ll be on it.


CllcanadaTop Poster CURE Hero in reply to Justasheet1

Yes combinations based on history... and we need to start cycling them... hopefully we will find something that can be cycled ever 3-5 years then it becomes more like an oil change... 😀


Does anyone have another link for this? It tells me I have to sign up for pro at $20 a month to read it.

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