The key question for the Company and its shareholders is…….. what is it going to take to get ultimate marketing approval for Veyondaâ, and how confident are we of achieving that end based on the current data?
That’s the context I believe is important that we all keep in mind in relation to the recent announcement of the DARRT-1 clinical trial data.
Current best practice
Marketing approval ultimately will rely on Veyondaâ being able to offer an advance on what currently is available.
In terms of what currently is available, in general terms these are the steps involved in the treatment of aggressive prostate cancer:
- STEP 1 is radiotherapy to the pelvic cavity to try and kill as many cancer cells as possible that have escaped from the prostate gland. This is where surgery has been unsuccessful in limiting the disease
- STEP 2 is hormone therapy that seeks to shut off the production of testosterone, the male sex hormone fuelling the growth of the cancer. When STEP 2 eventually fails, the disease is referred to as being castrate-resistant disease
- STEP 3 is chemotherapy (usually docetaxel and prednisone). By this stage, the disease typically involves multiple secondary tumours and is referred to as metastatic castration-resistant disease
- STEP 4 is additional anti-testosterone therapy known as androgen-ablation therapy, currently involving one of two drugs (abiraterone or enzalutamide)
- STEP 5 is palliative treatment including pain relief and low-dose radiotherapy to selective troublesome tumours.
DARRT-1 is not competing with STEPS 1-4. DARRT-1 is competing with palliative care.
We are aiming for the DARRT-1 treatment approach to be the new STEP 5, pushing palliative care down to STEP 6.
The patients in DARRT-1 have been through STEPS 1-4 and have reached the end of their treatment journey. There are no standard treatment options remaining. A clinical study is their only option.
For NOX, marketing approval will be based on showing that DARRT is better than palliative care.
With any new anti-cancer drug being developed for the treatment of late-stage cancer, including prostate cancer, the key primary end-points the regulators are looking for are:
- progression-free survival (stopping tumour growth, determined by how many subjects at a particular time-point are determined to have had no disease progression), and
- overall survival (determined by how many subjects are still alive at the end of the study).
In the case of prostate cancer, there also are a number of secondary end-points including:
- PSA response (based on a decline in PSA levels of at least 50% compared to baseline)
- Pain response (based on a decline in pain levels of at least 30% compared to baseline)
- Quality of life (a measurement of independent living).
Marketing approval can be granted on the basis of a mix of these primary and secondary end-points.
The DARRT approach
The patients in DARRT-1 have been through and have failed STEP 4. Failure being defined as the cancer progressing during STEP 4 therapy.
Prostate cancer mostly spreads to the skeleton, with end-stage disease typically involving dozens or even hundreds of tumours scattered in the pelvis, ribs, skull, arm and leg bones. Tumours in bone are characteristically very painful, generally requiring considerable opioid treatment. Tumours in the bones in the spine also can cause spinal compression and paralysis. Secondaries in tissues and organs outside of the skeleton are less common in prostate cancer, but generally involve lymph nodes in the pelvis and abdomen, and very occasionally the brain.
This is the state of the patients recruited into DARRT-1. These men have advanced, progressive disease that for the great majority of patients has only one inevitable outcome.
Our aim with DARRT-1 is to provide a significant therapeutic outcome for men with no remaining options – to do considerably more for these men than palliative therapy. At the very least, our aim is to shrink some of their tumours to provide pain relief; or even better, to put the disease into dormancy so that the men will live longer with a good quality of life, largely free of pain; at best we dare hope that some men will even be ‘cured’.
But longer life is not necessarily better life in cancer therapy, with many anti-cancer therapies coming with significant side-effects or involving extended and intrusive courses of treatment that mean patients are spending valuable time away from their families.
We have designed the DARRT treatment regimen to be:
- short (15 days)
- minimally invasive
- well-tolerated (no significant side-effects)
- employing readily available and relatively inexpensive radiotherapy procedures.
DARRT is based on the idea of using a combination of Veyonda (15 days) and a low-dose of radiotherapy (5 days) to trigger an immune response in a single tumour that will lead to resolution of the irradiated tumour, followed by the immune response then spreading out and leading to the immune system attacking and killing cancer cells throughout the body. A huge ambition that, if successful, potentially could revolutionise the treatment of prostate cancer.
The data we released last week gives us the confidence to believe that we are on track for success.
We started this dose-finding arm with 14 men, whose disease history would tell us were fated to continue to progress despite palliative care, with that care providing little or no impact on the course of their disease or their survival prospects.
Six months after we gave these 14 men a single course of treatment, the cancer in 8 of those 14 men has not progressed based on a radiographic review process known as RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). The process is based on MRI or CT scans and involves counting all observable tumours and measuring up to 10 individual lesions:
Progressive disease is defined as an increase of at least 20% in the sum of the longest diameter of measurable tumours, and/or the appearance of new tumours.
Stable disease is defined as a change in the sum of the longest diameters of measurable tumours between +19% and – 30%, and the appearance of no new tumours.
Given that we are seeing this durable effect lasting at least 6 months following a single course of treatment, we believe that it likely represents an immunological effect in combination with radiation, and almost certainly not a monotherapy effect of Veyondaâ. And given that the radiation was only applied to a single lesion, we believe that the general anti-cancer effect involving responses in non-targeted lesions, indicates an abscopal response.
That’s 8 of 14 men who history would tell us should have been considerably worse after 6 months. And we are going to follow these 8 men for the next year to see just how long their responses last.
Putting the data into context
The 6-month data we have reported on has 3 readouts: PSA response, pain response and disease control rates.
DARRT-1 is a sighting study only. That is, it is a single-arm study with no comparator arm. So, any projections about what might happen in a large two-arm study need to be seen in that light.
Nevertheless, we can compare the reported responses against historical experience.
- The PSA response rate (proportion of subjects experiencing a reduction of 50% or more in PSA levels) was 36%, versus reported rates of between 5-9% with low-dose radiotherapy alone.
- Five of 14 subjects reported experiencing a significant reduction in their pain at 6 months, including 2 men reporting to be free of pain. Our expectation is that palliative care with low-dose radiation would provide only minimal rates of improvements in pain levels this long after treatment.
- Having 8/14 patients with progressive disease showing no disease progression at 6 months, suggests that this would have a significant effect on a mean progression-free survival outcome.
Together, these three outcomes suggest that if maintained in a large study with a comparator arm, Veyondaâ would be potentially likely to provide an anti-cancer effect warranting marketing approval.
Finally, it’s worth noting two things:
- First, that the data comes from all patients across 3 different dosages (400, 800, 1200 mg) of Veyondaâ. Patients in the second arm of the study that we will report on in the second half of 2019 are receiving the highest (1200 mg) dose;
- Second, that these meaningful anti-cancer outcomes were achieved with a single course of treatment. There is no apparent reason why DARRT treatment cannot potentially be repeated as needed to provide an extended response.