New Drug!!

[EastBayDad]

Anyone else see this article this morning? This seems like great news. Right? My understanding is that this is super charged Venetoclax.

finance.yahoo.com/news/inno...

[SofiaDeo]

Great, another one! IDK about "supercharged" so much as, a new one. There are more:

clinicaltrials.gov/study/NC...

clinicaltrials.gov/study/NC...

clinicaltrials.gov/study/NC...

clinicaltrials.gov/study/NC...

clinicaltrials.gov/search?c...

Most of these are in China, with 2 expanding outside that region to include the US.

[scryer99]

and another... a few board posters, including me, are in clinical trials on this one.

clinicaltrials.gov/study/NC...

Results of Phase 1 are still ongoing (I remain in treatment in that trial), but promising enough that BeiGene are moving directly to a Phase 3 trial application.

"Supercharged Venetoclax" is a roughly accurate description. More precisely, BGB-11417, since named Sonrotoclax, is estimated to have 10x the potency of venetoclax, with a shorter half-life which means they can more precisely control dosing. Targeting and off-target effects are thought to be in similar range.

Ramp-up, in trial at least, was quite slow, taking 6-8 weeks to get to full dosage. I've been on them for 11 months now, in combination with zanubrutinib which was also administered 3 months before trial start.

I've had a good experience, although my progress against CLL has been slower than some other patients in trial. Side effects have been manageable, mostly skin and GI issues of low to moderate grade. Several participants have walked out the door within 8 months with uMRD (undetectable minimal residual disease). That does not mean a cure, but it is thought to correlate with a lengthy remission.

BCL2 inhibitors are another tool in the toolbox. And the more of those we have, the better a chance of survival and good quality of life while the research further advances.

[Skyshark in reply to scryer99]

I would have thought a short half life was a problem. Possibly needing to take the tablet 3 or 4 times a day to maintain area under the curve with very high spikes in blood concentration.

While drugs with a long half life like Obinutuzumab are once every 28 days.

[SofiaDeo in reply to Skyshark]

Mmmm I think shorter half life drugs can either get modified, or be formulated as a controlled release form, to get around this. It's more problematic with extremely long half life agents.

pubs.acs.org/doi/10.1021/ac...

Some of the psych drugs, as well as pain meds, use immediate release formulations until the desired effect is reached, then a patient is switched to sustained release. A number of blood pressure and heart meds offer these options, too.

As the number of CLL patients continues to rise, perhaps we may one day have a few of these options. Not that it's great our numbers would have grown so much that manufacturers find it profitable to accommodate us like this.

[neurodervish in reply to SofiaDeo]

Is it possible our ranks have grown because overall survival rates have gotten better? I try to stay optimistic and wonder if newer therapies (+ diagnostic testing for more optimal tx options) have helped shift the stats.

[scryer99 in reply to Skyshark]

I don't think so... I'm not a doctor though, just some good statistics background.

If your half life is, say, 1 day, then a week in you'll have 1/2 + 1/4 + 1/8 + 1/16 + 1/32 + 1/64 = 63/64 of a full dose in your system when you take your next dose... but will be roughly steady state at that point each day from there on. So your drugs in system will vary from 2x dose to 63/64x dose over time. Plus, as SofiaDeo posts, they can play with controlled release mechanisms. So doctors/pharmacologists end up with finer grained options to manipulate the drug-in-system dosing if your half-life is shorter.

[SofiaDeo in reply to scryer99]

I wonder if the neutropenic and other cell line effects are having docs prefer shorter half lives. It may be more inconvenient to take more of an Immediate Release dose initially, but if one has untoward side effects, the drug is gone from your system much faster. And then use of marrow support drugs may decrease, if the marrow isn't greatly suppressed from a longer lasting med. This would ultimately decrease the risk of severe Side Effects for patients. It's somewhat annoying to take multiple pills, multiple times a day, but that allows docs to individualize doses, and titrate a dose to specific patient effect.

Another consideration for using short half life drugs, at least for early trials, is to be cautious until they see how a drug actually distributes into body tissues. Until you know a chemical's Volume of Distribution, from the 1a trials, you really don't want drugs with a long half life IMO. A Volume of Distribution is a number that refers to how the drug disseminates into other tissues as compared to its concentration in the blood. Some drugs do leave the blood stream and accumulate in tissues. This can be useful when that is wanted, but it's not always wanted.

ncbi.nlm.nih.gov/books/NBK5...

Researchers may estimate a volume of distribution from a chemical structure, and animal models, and there are other prediction tools to aid in initial estimates. But they won't really know whether it actually stays mainly in blood & lymph tissues (which probably would be desirable in a drug for CLL) or diffuses into body fat & other organs, where it may accumulate. If there is an adverse reaction to a long half life drug, a patient is at higher risk. It will take longer for that drug to be eliminated compared to a shorter acting drug. Since some of these newer mechanism of action CLL drugs are "new chemical agents" we don't 100% know how they actually will distribute into the body. The early mouse and test tube reactions and other tools give researchers an idea, but it needs to be verified in vivo. That's what the 1a testing does. We know promising agents may end up not working well or being feasible (look at ivermectin) in real people.

So a Phase 3 trial, is generally seeking to find out if one treatment works as well or better than a known treatment. I believe Phase 3's are what the iwCLL guidelines are often referring to, when you read in the treatment algorithm "consider a patient trial" for previously untreated CLL. No one is generally pushing patients undergoing their very first treatment to try something completely unknown.

From ASH iwcll guidelines: ashpublications.org/blood/a...

"Eligibility criteria for clinical trials

The selection of CLL patients for clinical trials is similar to that for patients with other malignancies. Phase 1-2 clinical trials commonly, although not invariably, are intended for patients who have received prior therapy. The inclusion of patients with SLL in clinical trials for CLL is encouraged. The combination of new agents with standard therapy as part of phase 2 studies may be investigated in both untreated and previously treated patients. Phase 3 clinical trials are used to compare the clinical outcome using new treatment modalities with that attained using current standard therapy. Other requirements for eligibility with respect to age, clinical stage, performance status, biomarkers, organ function, or status of disease activity should be defined for each study"

So depending on other diseases, or how ill one is, you may not even qualify for a trial. You have to be ill enough, but not too ill!

[scryer99 in reply to SofiaDeo]

”Some drugs do leave the blood stream and accumulate in tissues.”

Now that you mention it… that’s been a problem with BGB-11417, at least in my case. One of the skin side effects has been TEC, for which I take a couple of prescribed antihistamines and topical steroids which mostly manage the issue. The theory has been that accumulated drugs essentially are leaking out through sweat and causing skin irritation. Nothing permanent so far, but some impressive rashes.

Well, I knew what I was getting into with a 1B trial. The overall trial results have been quite good though even if my personal results have not quite hit that mark yet. But the level of care and attention has been excellent and I’m making headway against cancer - no regrets overall.

[EastBayDad in reply to scryer99]

Thank you for letting us know about this interesting trial. Two questions?

Is the thinking that Sonratoclax will cause create longer remissions or shorter duration treatments than Venetoclax?

I have several friends who took Venetoclax and are currently on “remission”? They are planning to take Zanubrutinib as their next treatment. If you take Sonratoclax/Zanubrutinib at the same time, is there a concern that there isn’t a good next treatment?

[AussieNeil Administrator in reply to EastBayDad]

The advantage of combination, fixed term treatments, is that it's difficult for CLL sub-clones to arise which have resistance to all the treatment drugs. Any new sub-clones face extremely high odds against incorporating DNA copy errors that simultaneously confer resistance to more than one drug. That means that following any successful combination treatment with a reasonable remission time, there's a very high probability that we can repeat that treatment, perhaps several times, before needing to find a different next treatment. It's going to take up to a decade or so to find out how often the same combination treatment can be repeated - and that's before exploring changes to one of the combination drugs, e.g. venetoclax to sonrotoclax, rituximab to obinutuzumab, one of the covalent BTKis to a non-covalent BTKi (currently only pirtobrutinib) and so on, eliminating just the drug to which resistance has developed.

As to whether "Sonratoclax will cause create longer remissions or shorter duration treatments than Venetoclax", that will be interesting to see. The venetoclax dose needed to be ramped up to reduce the risk of Tumour Lysis Syndrome, because it is so effective at rapidly killing CLL cells, yet venetoclax based treatments are typically a year long, compared to the 6 cycles (24 weeks) of the older combination chemoimmunotherapy treatments (bendamustine + rituximab (BR) and fludarabine, cyclophosphamide and rituximab (FCR).

Neil

[SofiaDeo in reply to AussieNeil]

I think that the older, standard chemotherapeutic agents needed to hit the cancers like a ball peen hammer, to knock them out quickly before they overtook a patient. So treatments were hard but needed to be short, patients couldn't tolerate extended treatment.

I liken CLL treatment as more of a "rubber mallet" approach. We don't need a ball peen hammer, we can do a more delicate, nuanced attack on CLL and not suffer the severe side effects standard chemotherapy has.

[scryer99 in reply to EastBayDad]

My thinking going into trial was as AussieNeil describes. I had a strong bias towards fixed treatment periods. Being relatively young, signing up for indefinite treatment duration did not make sense to me with a cancer known to eventually evolve resistance to ongoing treatment. That is fine when you are 75 and BTKi drugs are less wear and tear. Not so good at 55 when it’s going to take a couple more decades to pay college tuitions and marry off my pistol of a daughter.

The reason for combination therapy in my case, in addition to stacking up drugs all at once to reduce treatment duration and ward off mutations, was practical. I had a high progression rate and massive spleen swelling. Hitting the system with a powerful BCL2 inhibitor with no prep would have been high risk for tumor lysis syndrome, a situation where your system is overwhelmed with the sludge from dead cancer cells all knocked loose at once. That can be fatal if not managed. Taking zanubrutinib as pre-trial prep knocked the cancer down a bit, lowering TLS risk. It’s been effective in this trial; 0 TLS incidence so far and I am patient 177.

As far as downstream treatments, there’s enough options and treatments in pipeline that I felt comfortable with that risk. It’s not a given that other BTKi and BCL2 options are off the table. I thought the potential upside of getting to uMRD, without the significant downside risk of FCR chemotherapy, was worth the trade. Still looking that way, even with the recent news that I will need a second year in trial.

I also looked at trial as a means to access the latest drugs in a setting with maximum doctor attention and diagnostic funding. Zanubrutinib was not standard of care when I started but was in late stage trials and looked solid. BGB-11417 as a more powerful BCL-2 seemed to me to be a good bet, vs. an entirely novel mechanism. I would not have considered a novel mechanism as a first line treatment, and even going into a Phase 1b with known good treatment routes was not without risk.

[EastBayDad in reply to scryer99]

Thanks for this excellent overview. I am also 55 and have a pistol of a 12 year old. I am meeting with my UCSF CLL specialist on Monday for the first time. I will definitely bring up your trial and the newly approved CAR-T therapy.

[DriedSeaweed in reply to EastBayDad]

The BGB-11417 is now called Sonrotoclax.

There is actually a new trial: Study of Sonrotoclax (BGB-11417) Plus Zanubrutinib (BGB-3111) Compared With Venetoclax Plus Obinutuzumab in Participants With Chronic Lymphocytic Leukemia (CLL)

clinicaltrials.gov/study/NC...

If this is the Alliance trial I heard about then Dr. Jennifer Brown of DFCI designed it. If not, another S+Z trial might be in the works too.

The trial Scryer99 might be on is: Study of Bcl-2 Inhibitor BGB-11417 in Participants With Mature B-Cell Malignancies

clinicaltrials.gov/study/NC...

This trial is in part 6 where sonrotoclax could be combined with obinutuzumab with/without zanubrutinib.

”Experimental: BGB-11417 + Zanubrutinib Combination Therapy Dose Expansion: Part 6

Participants with treatment naïve CLL/SLL will receive oral BGB-11417 at an RP2D dose to further define the safety profile in combination with obinutuzumab without and with zanubrutinib.”

[scryer99 in reply to DriedSeaweed]

Yes, that’s the new Phase 3 trial which is the successor to the 1b trial me and a few other posters are in various arms for.

I have not reviewed all results of the 1b other than what was published at the most recent ASH conference. Anecdotally at least in the various arms of Phase 1b, Sonrotoclax / BGB-11417 in combination with Obintuzumab / Gazyva seems to be getting excellent results even against problematic genetic indicators. A lot of folks got to get out of school early in that cohort.

[Skyshark in reply to EastBayDad]

There is very little point in discussing CAR-T at first appointment. At a minimum it's a 3rd line treatment for patients that are relapsed/refractory to both BTKi and BCL-2. This is when the shit hits the fan, the novel drugs no longer work, far better to never reach the stage of being double refractory. With current approved drugs it's to be hoped that double R/R is somewhere after 20 years from start of first treatment. For u-CLL with del17p/TP53mut or those with complex karyotype it may be 15 years.

Yet to be approved for NHS, it's in progress, which is a step up from awaiting development. They have approved CAR-T treatments for other diseases.

nice.org.uk/guidance/indeve...

The UK has over a hundred hospitals that treat CLL, CAR-T is limited to a few specialist hospitals. (The one that isn't in both lists for under/over 25 is Great Ormand street, a specialist children's hospital.)

england.nhs.uk/cancer/cdf/c...

[EastBayDad in reply to Skyshark]

My doctor and his colleagues are very involved in CAR-T therapy. I am a science geek. Fascinating stuff.

What is 20 years to R/R based on? Two treatments of BCI and one treatment of a second generation BTK? That number is much longer than I have heard.

[Skyshark in reply to EastBayDad]

u-CLL with ATM del and SF3B1 mut, started with VenO last April, I'm very much hoping to reach median. (For m-CLL all these numbers can be x1.5 - 30 years.)

I'd hope for 3 rounds of BCi+mab. First 12 cycle VenO 5 years drug free 6 years to next treatment, 2nd line 2 years VenR - 3 years drug free - 5 years to next treatment, 3rd line 2 years VenR again, 1 year drug free 3 years to next treatment, cBTKi 3.5 years, ncBTKi 1.5 years.

Or 1st line Ven + Ibrutinib, then VenR twice, cBTKi, ncBTKi no significant difference.

Or start with cBTKi 8.5 years, ncBTKi 1.5 years, 3 rounds of Ven+mab.

Currently short duration triple combinations BCi+BTKi+mab are only in trials, AVO trial randomised to FCR. Results from AVO are limited by observed data cut off to about 6 years but median can be projected to well in excess of 15 years on first line.

[Phil4-13]

EastBayDad, always glad to hear of new treatment discoveries. It's wonderful. Thanks for sharing. 🙂 Sandra

[Kiwidi]

Thankfully it is available here in Aotearoa NZ too where we have little access to any of the more recent drugs as first line treatment. Almost wish I needed treatment but know that that’s pretty dumb. Hopefully if/when I need it there will be something similar available or I’ll be selling up and moving to Australia.

[EastBayDad]

Busy, busy week on CLL front. So psyched to see this news.

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