This story was first published in CLL News June 2018 

At the Leukaemia Foundation-hosted New Directions in Leukaemia Research (NDLR) conference in Brisbane in March 2018, Dr Mary Ann Anderson, a clinician scientist at the Walter & Eliza Hall Institute of Medical Research (Melbourne), shared a story about the development of venetoclax (Venclexta®). It involved research by thousands of people over 30 years resulting in a paradigm shift in the treatment of CLL that is “tangibly changing people’s lives”.

How did you become interested in blood cancer research?

What struck me as a haematology registrar was – we have great treatments and can cure some people but there are many diseases where patients don’t have good outcomes. I found it particularly challenging when we didn’t have therapies for people and couldn’t help them. The natural next step in my career was working to get better treatments for those people. The only way to do that is through research, so I went into a PhD. I’ve been extremely fortunate to be involved in the development of a new drug that has helped a lot of people and I’ve fulfilled my career goal doing that. Sadly, we still have unmet areas of need that means I’ll be employed for some time in the search for better treatments.

What was your presentation at NDLR about?

I shared a wonderful story about the development of a new drug called venetoclax (formerly known as ABT-199) that I’ve only been involved in for the last seven years but which started in 1984 when a protein called BCL2 was discovered. Over the 80s and 90s, BCL2 was shown to be pivotal in driving cell survival, keeping cancer cells alive inappropriately, making cancers develop and being insensitive to chemotherapy. Researchers at WEHI, in collaboration with AbbVie and Genentech, developed a molecule that selectively binds to the abnormal BCL2 protein to take out its function. I started my PhD in 2011 and together with Professor John Seymour and Professor Andrew Roberts at Peter Mac and Royal Melbourne we gave venetoclax to the first three patients in the world. We knew within hours that this drug worked. They all had dramatic and rapid clinical responses.

Describe your role in the discovery process.

I started my PhD six months before we dosed the first patient. In the laboratory, I tested CLL cells against venetoclax and they died very sensitively, suggesting the drug may be effective. I also looked at how the cancer cells were dying and found evidence this was a result of BCL2 being inhibited by the venetoclax. That’s what we call an ‘on-target’ effect. Then we gave it to a person and saw almost instantaneously that it was working. As well, using translational cells taken from these trial patients prior to dosing, then 8 and 24 hours after dosing, we could see the cells were dying via apoptosis (through the inhibition of BCL2), so we recapitulated in the lab what we were seeing in the clinic and vice versa.

How did you feel when you saw the ventoclax response in the lab?

It’s important you don’t get carried away. To me it’s… ‘ok, it works in the lab, that’s great; will it work in people?’ It was only when we gave it to the first few people, and saw their white cell counts falling from 40 to 2 in a matter of eight hours, that I allowed myself to think – ‘wow, we really might be on to something here’. I was really lucky, it was only a matter of six months from seeing it work in the lab to actually seeing it work in a person. There was also a lot of work at AbbVie to test its safety and a lot of other work by colleagues to underpin the safety of the drug.

What was your involvement in the first venetoclax studies?

Looking after patients was my main role in the early phase studies where safety is the primary consideration and end-point. Patients must be monitored really closely and often have other health issues as well. It was day-to-day medical work, made richer by the fact I was taking cells from my patients and looking at how they died in the lab in response to this drug. I’d see the patient and look at their cells in the lab, then see the patient again the next day. For me the two really played off each other, so I was hopefully better informed about my patients and how they might respond by my laboratory work, but at the same time I was being driven to do my laboratory work by seeing the patients and how well they were responding. These patients voluntarily agreed to donate their cells for research purposes. Without many patients over decades donating their cells so we could study them in the lab, we would not have these drugs. That’s something that should never be underplayed, the importance of patients altruistically donating their samples for science that has given us these new discoveries.

What was the outcome of that first venetoclax trial?

It was a very successful Phase I clinical trial. In contrast to most Phase I studies, we showed venetoclax works in about 80% of CLL patients and we can get rid of all evidence of disease in 20% of them. The way we think about CLL is radically changing as a result of this new therapy. We no longer just want to control the disease. For the first time people are wondering if we can cure CLL with tablets rather than going on to allogeneic transplant. The main side-effect we identified was that all three of the first patients who received this drug developed a complication called tumour lysis syndrome (TLS) – where cancer cells are destroyed too quickly. While you never want to see complications, for a first-in-human trial, this was both worrying and extremely exciting, and an incredibly powerful indicator that the drug was working too well. We’ve got protocols to manage the risk of TLS now and it is rarely seen.

What’s happened since?

Many patients relapse after about two years on venetoclax as a monotherapy. In the next suite of trials we combined venetoclax with monoclonal antibodies such as rituximab or obinatuzumab, or with other novel agents such as ibrutinib. Patients on combination therapy achieve deeper responses. Rather than a partial response, they’re achieving a complete response, and instead of just achieving a complete response, they’re actually clearing all evidence of disease; a state we term minimal residual disease (MRD) negative. These deeper responses correlate with longer periods before patients relapse. In some patients, we can actually stop treatment and some have enjoyed prolonged periods without treatment, where the disease has not come back. It’s starting to remind us of what happened with CML*. It’s very early days, we don’t yet have strong evidence that it’s safe or the right thing to do, but it’s something we’re starting to explore in our clinical trials.

What other areas of research are you are working on?

In the lab I’m trying to identify which patients are more likely to have good responses and also those who are more likely to have bad responses. We are doing a series of molecular tests to see if there’s a way we can prospectively identify the patients who aren’t going to do as well, and selectively target those patients for more intensive therapy. I’m also interested in trying to understand why resistance develops so we can look at targeting it more effectively. We don’t yet have a good biomarker (a laboratory test that predicts for a poor outcome) so another approach is looking at the micro-environment. CLL can sit in the bone marrow, lymph nodes and blood. There’s strong evidence that CLL in a lymph node is protected from death by any agent due to its environment. The stroma (tissue) and blood vessels help to keep the CLL cells alive and sustain them. When we look at CLL cells on an artificial stroma, in an artificial micro-environment, they are resistant to death by venetoclax. Early evidence from my colleagues suggests you can overcome this effect of the microenvironment niche by combining venetoclax with ibrutinib.

What aspect of this research excites you the most?

The thing that gets me up in the morning is finding new and better ways to help people. A few years ago I’d have to say – “I have nothing for you”. Now I’m saying to more and more of my patients – “I actually have something that can help you, a new drug, with good evidence that your disease will respond”.

What is the role of clinical trials?

They are essential and have different roles in different patient groups. When patients get to a point where there aren’t any conventional therapies, then a Phase I trial is particularly attractive. They are always ethically approved, based on evidence the drug is likely to be safe and effective. That doesn’t mean they will be and sadly sometimes they’re not. But we offer Phase I studies to people who have no other options and occasionally we find a venetoclax and we give people a prolonged period of disease-free survival. We always hope the next venetoclax is around the corner. To people asking if they should go on a clinical trial, I say: “it may help you and we really genuinely hope it does but if it doesn’t help you it will help people down the line”. Knowing a drug by itself doesn’t work is still valuable information, so we don’t use it on other people going forward. For patients on a trial, there are elements of ‘there is something in it for me’ because they might get a drug that will work, as well as altruism because they’re helping science and those people who come after them. It’s often easier to sell larger Phase II and III studies to patients where the drug has good safety evidence and a signal of efficacy. But as a basic scientist I find Phase I studies the most inspiring. They’re the ones where people are in the most need and that are bringing the next big thing to our attention.

What is the next big thing?

I think it’s going to be combinations. We’re already doing trials of combination therapies – monoclonal antibodies with novel agents, dual novel agent therapies, and potentially the holy trinity, as John Seymour puts it – two novel agents and a monoclonal antibody, or potentially down the track, even combining chemo-immunotherapy with novel agents. That’s where I think we’ll end up, with these very deep responses and potentially options of cure. There are always new drugs in the pipeline and it remains to be seen how they all fit together. A challenge is integrating evidence from lots of different trials, to find out where in a patient’s journey we should use these agents. They’ve been used traditionally in the relapsed/refractory setting but maybe they’ll be more effective in the frontline setting.

Venetoclax – a 30-year story

1984: BCL2 protein discovered

2011: First patient dosed with venetoclax

2016: Venetoclax FDA-approved in the U.S.

2017: Venetoclax TGA-approved in Australia

1 March 2019: Venetoclax listed on the PBS in combination with rituximab for relapsed/refractory CLL

“It’s decades and decades of work by very many clever and very intelligent people – chemists, structural biologists, basic science biologists, translational scientists and clinicians,” said Dr Anderson.

“It’s work at places like the WEHI and by industry like Abbvie and Genetech and in academic research hospitals like Peter Mac and Royal Melbourne.

“It’s a body of work that’s taken thousands of people, in a rich variety of backgrounds, to come to fruition.”

* Treatment-free remission is possible for many people with CML.