Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Multiple Myeloma’

Going beyond BCMA as a target in multiple myeloma

With the startling news this morning that Poseida Therapeutics are abandoning their IPO plans and pursuing a different tack with a $142M investment from Novartis to fund clinical trials for their BCMA-directed CAR T cell therapy program in multiple myeloma, our attention is focused yet again on the highly competitive BCMA niche.

Poseida’s data was revealed at ASH last December and with an ORR of 63%, the initial efficacy was a bit lower than we have seen from rivals Bluebird Bio and Legend/JNJ, although the Penn/Novartis construct reported disappointingly lower responses in a small cohorts of patients, which may explain Novartis’s interest.

There are also other companies/products in this niche including GSK’s ADC, GSK2857916, and Amgen’s T cell bispecific, AMG 420, plus plenty of others with BCMAxCD3 bispecifics who have earlier skin in this increasingly highly competitive game.

Is BCMA enough though?  Is it really the answer to multiple myeloma or are there other approaches that might be better?

Putting new CARs in the spotlight

What of the future for CAR T cell therapies in myeloma beyond the initial generation 2.0 constructs?

We saw a vision for how this market might evolve and sought out some experts to learn more about what they are doing in this niche – what they had to say was really interesting.

After all, as Wayne Gretsky would say, don’t skate to where the hockey puck is (now) but where it will be… that’s a great analogy one cannot resist borrowing for the future of cell therapy in multiple myeloma.

In our latest article, we go beyond BCMA to explore where we think the field might be going and why a tunnel focus on BCMA might not be such a great thing…

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New developments in Multiple Myeloma

We have been following the progress of various classes of molecules in the myeloma space here on BSB since 2010. These include traditional approaches (e.g. HSCT and proteasome inhibitors/IMiDs and various antibodies or ADCs), as well as immunotherapy (checkpoint blockade, CAR T cell therapy, oncolytic viruses etc).

Brick Lane Grafitti

There’s much going on in this space and it’s not only becoming extremely crowded and competitive (akin to 1L NSCLC), but there is a gradual trend towards convergence on many fronts, be they targets or modalities.

In our latest look at the myeloma space, we focus on several key areas of development – antibodies, CARs, and also highlight a new target that may be of interest…

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Learning from IO-IO combo misses

In the frantic rush to the clinic with various IO-IO combinations, many people seem to have forgotten that these have an increased risk of failure than say, combining one IO molecule with chemotherapy.

This risk can take the form of increased toxicities, as well as lack of efficacy, especially if you are giving an unknown therapy instead of one that is known to be effective in controlling the tumour.

We look at a tale of two cities in lung cancer; there are some interesting lessons to be learned here…

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The Future of Multiple Myeloma

Happy New Year!

Immunotherapy treatment for multiple myeloma has been around for several decades, first in the form of stem cell transplantation, then augmented by the addition of IMiD immune modulation drugs such as thalidomide, lenalidomide or pomalidomide. In due course, along came immune checkpoint blockade in solid tumours and it was only a matter of time before they would be evaluated in hematologic malignancies, albeit with mixed results.

The proteasome inhibitors and IMiDs are unlikely to go away any time soon, but other targets have also emerged including CD38, SLAMF7/CS1, BCMA/APRIL, PD–1/L1 and a few others that are being currently investigated in the clinic.

Where does this leave us and what looks really promising?

In our latest thought leader interview undertaken at the recent American Society of Hematology (ASH) meeting in Atlanta, we asked a global expert for his candid views and were not surprised at some of the hard hitting comments that emerged from the in-depth discussion of several key issues…

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The science behind the venetoclax clinical trial strategy

Buried amongst the intense hurly burly of a major medical meeting such as the American Society of Hematology (ASH) are the unsung preclinical researchers whose work largely makes clinical development possible. After all, few sensible companies would bet on an expensive clinical trial program, especially in combination, without first knowing whether such an approach is rational or not and has a decent shot of working efficaciously.

At stake here is the potential for building a blockbuster cancer drug niche by niche.

Venetoclax (BCL-2 inhibitor) got off to a somewhat slow start compared to say, ibrutinib (BTK inhibitor), which had a much broader initial indication and a lower risk of tumour lysis syndrome (TLS), yet it may actually have a wider application across multiple hematologic malignancies. This could well end up as one of those classic tortoise versus hare stories in the long run.

Back in 2013, we posted five interviews conducted with a range of experts including:

  • Dr Oliver Sartor (prostate cancer)
  • Dr Susan O’Brien (CLL)
  • Dr Deepak Sampath (BCL-2 and ABT-199)
  • Dr John Jenkins (then deputy director at the FDA)
  • Dr Renier Brentjens (CAR-T cell therapy)

To put this in context, consider that we just recorded 15 interviews at ASH this year alone!

As regular readers know, we like to follow people and R&D stories over time, so while in Atlanta at ASH17 we took the opportunity to move a particular story forward – we wanted to learn where Dr Sampath and his colleagues are now and also where they are headed next. This gives readers a head start on anticipating what future clinical developments might be mentioned at JPM18 by either Genentech/Roche or AbbVie.

In our latest expert interview, we pick up and continue the discussion with Deepak Sampath to find out what’s happening with venetoclax four years on… it turns out quite a lot and makes for very interesting reading indeed.

Dr Deepak Sampath (Genentech)

Curious to now more about what this scientist and his work in BCL-2 targeting is all about?  Check out this short excerpt:

 

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Commentary on ASH17 Day 2 in Atlanta

Snow at GWCCAtlanta – it’s day 2 of the annual meeting of the American Society of Hematology (ASH) meeting here in a chilly and snowy Atlanta.

I have to confess snow is not something we normally associate with southern States such as Georgia, but a cold snap has taken it’s toll on the ASH meeting, with many presentations cancelled as a result of travel delays.

Sunday at ASH is well known for the plenary session that takes place in the afternoon, but what else is hot at the meeting today? We’ve been talking to thought leaders, spending time in the vast poster hall and hearing some oral abstracts. There’s been been a surprising amount going on today at ASH in Atlanta.

If you are at ASH then you’ll know that all the sessions end at the same time, resulting in a massive movement of people as they go to the next session, as we saw today:

 

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The dawn of a new beginning for Cellectis?

Paris – amazingly it’s now 3 years since we interviewed Cellectis (NASDAQ: $CLLS) CEO André Choulika and CSO Philippe Duchateau (See post: Can Cellectis revolutionise CAR T cell therapy):

Cellectis CSO CEO

Cellectis Senior Management – Drs Duchateau and Choulika

Since then, we’ve followed the company over time, including an interview with one of their leading scientists, Dr Julianne Smith at ASH 2014, followed by the initial results of their first allogeneic CAR T cell therapy UCART19 presented at #ASH15 by Professor Qasim.

It’s hard to believe 3 years have gone by so quickly! As regular readers know what we often do on BSB is follow stories longitudinally, so while in Paris for an Immuno-Oncology Summit we thought it a rather timely opportunity to revisit Cellectis and take stock of where they’re at and ask what the future may hold for them?

With the recent news that Gilead have acquired Kite Pharma, there’s going to be a lot of interest in what companies such as Cellectis are doing to bring allogeneic “off the shelf” CAR T cell therapy to market.

This is the penultimate post in our summer mini-series on gene editing and allogeneic CAR T cell therapy and features a candid interview with Dr Philippe Duchateau, Chief Scientific Officer, at Paris based Cellectis.

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Novel Targets in Multiple Myeloma

Much of the focus in multiple myeloma over the last decade has focused on two key drug classes – proteasome inhibitors and IMiDs – with some recent approvals for monoclonal antibodies targeting key proteins on the surface of malignant myeloma cells such as CD38.

#ASH16 in San Diego

Combinations of these core therapies have lead to a noticeable improvement in outcomes for people living with the disease – from 3-4 years over a decade ago to now approaching 10 years post diagnosis.

If we want to continuously beat the status quo and improve on the chronicity, however, it is likely that several things will need to happen:

  • Better understand mechanisms of resistance that induce relapse
  • Develop predictive biomarkers of response
  • Identify novel therapeutic targets

Here. we focus on the latest preclinical findings that were recently presented at the American Society of Hematology (ASH) in San Diego and explore where the future might be headed in this disease.

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September BSB Reader Mailbag

After some relatively quiet summer months, we have been deluged with questions and requests this month for commentary on some hot topics of late. This seems like a good time to take stock and reflect on some of most frequent ones sent in.

west-acton-tubeThe original Journal Club post slated for today will appear next week instead.

Here, we address numerous queries on the following five topics readers are interested in:

  • APHINITY trial in HER2+ adjuvant breast cancer
  • Array’s BRAF plus MEK data in metastatic melanoma
  • Kite’s interim ZUMA–1 phase 2 announcement
  • Amgen’s Kyprolis in newly diagnosed multiple myeloma
  • BMS nivolumab data in 1L lung cancer (CheckMate-026)

The last two in particular seem to be causing a lot of hand-wringing!

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ASCO 2016 Preview 1 – Novel Combination Approaches

For years we’ve followed the trials and tribulations of targeted therapies seeing many approved and quite a few disappear forlornly (and officially) off to dog drug heaven. Many more sit in no-man’s land as companies eagerly wait in a holding pattern for other trial readouts in different tumour types. Sadly, sometimes these studies don’t generate enough compelling data either. With so much competition about, there are no shortcuts or low-hanging fruit in biotech or cancer drug development any more.

ASCO16 Chicago 1

En route to Chicago and ASCO!

Then along came antibody drug conjugates (ADCs), with some encouraging results in a range of cancers in both solid tumours and hematologic malignancies that lead to the approval of several new therapies.

After that, the next big advance was immunotherapies, specifically checkpoint blockade, with encouraging single agent activity in melanoma, lung, and even urothelial bladder cancer. We’ve also seen the promise fo combining two different checkpoints such as nivolumab and ipilimumab together in metastatic melanoma, albeit with an increase in toxicities.

This is all very well and good, although the challenge remains that the majority of patients either respond to therapy and relapse, or do not respond at all, depending on the circumstances, the tumour type and the regimen. We still have a long way to go in moving the needle and creating a new paradigm shift on a broad scale.

So what happens when we start to combine modalities – such as targeted therapies with immunotherapies?

Uh-oh, I hear the distant cries of disagreement erupt…

  • Remember vemurafenib plus ipilimumab in metastatic melanoma was scuppered by severe hepatitis?
  • What about osimertinib plus durvalumab in NSCLC and the increased incidence of ILD?

Both of these statements are true, and yet… we should not assume that all mixed therapy combination approaches are doomed on the basis of a mere n of 2. What happens if some are synergistic or additive? What happens of there are hidden gems that teach us new ways of doing things rather than doing the same old thing just because it’s always been done that way?

With this in mind, I’d like to open the door on our first ASCO 2016 Preview series with a look at novel combination approaches in development that caught my eye.

What are the early hints and signals that we can learn from the data? Which companies are evaluating imaginative new ideas that may turn the tables on traditional thinking?  The ideas discussed here may well surprise a few people.

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