CEO Blog: Timelines and Strategies

With NOX66 running in 3 separate clinical programs, there is considerable scope for priorities, commercial strategies, timelines etc to become blurred in shareholders’ minds. Hopefully this will make it clearer. …………………………………………………………………… In terms of priorities: The DARRT program in prostate cancer is #1. We regard this as our primary path to market approval and a […]

With NOX66 running in 3 separate clinical programs, there is considerable scope for priorities, commercial strategies, timelines etc to become blurred in shareholders’ minds.

Hopefully this will make it clearer.

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In terms of priorities:

The DARRT program in prostate cancer is #1. We regard this as our primary path to market approval and a considerable amount of effort is going into seeking to make that happen.

The LuPIN program is #2 in priority.

The DARRT program in cancers other than prostate cancer is #3.

The CEP program is #4 in the queue after the 3 radio-enhancing programs.

This priority ranking has nothing to do with our perceived likelihood of success. It has all to do with what we believe is the quickest, surest and least expensive way to reach the market. It is a well-reasoned commercial strategy with an eventual successful launch of NOX66 onto the market in 2022 in mind.

All 4 programs are continuing, just at different speeds. The strategy is that data from all 4 programs then will feed into the successful launch of NOX66 on the market, helping raise the profile of the drug.

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In terms of commercial strategies:

Our objective is to bring NOX66 to market as the first well-tolerated, effective enhancer of radiotherapy.

Radiotherapy is the most cost-effective form of cancer therapy. It is generally of short duration (days and weeks vs months with chemotherapy), is relatively inexpensive (vs high cost of many modern chemotherapy drugs), is available in most countries irrespective of their economic situation and can be curative where the cancer is locally confined. It is when the cancer becomes metastatic and spreads beyond the site of origin that radiotherapy generally switches from being potentially curative to being palliative (non-curative).

NOX66 makes cancer cells about 3 times on average more sensitive to radiotherapy, and our objective is to use that power of NOX66 to shift radiotherapy from being palliative to being curative in more patients. This sensitising effect is the equivalent of being able to increase the dose of radiotherapy 3 times to the cancer, without increasing the dose or damage to healthy cells.

There are about 14 million new cases of cancer diagnosed globally each year of which roughly half are thought likely to benefit from radiotherapy. A high proportion of those 7 million patients each year is the potential market opportunity that NOX66 is chasing with a first-to-market, well-tolerated radio-enhancer.

The DARRT program is the way in which we hope to prove in the first instance the benefit of NOX66 as a radio-enhancer. This involves adding NOX66 therapy to patients with late-stage metastatic cancers that are being treated on a palliative basis with externally delivered radiotherapy. The general aim of palliative radiotherapy is to shrink a small number of larger tumours that might be causing pain or interfering with the function of a vital organ.

What we are hoping to show is that NOX66 is capable at the very least of delivering a greater and longer-lasting response of the irradiated tumours to the radiotherapy. If we can achieve that, then we believe that NOX66 has the potential to transform the practice of radiotherapy.

But there is a higher aim as well, and that is to achieve an across-the-body response in both irradiated and non-irradiated tumours in as many patients as possible. This being the much sought after so-called abscopal response. A positive abscopal outcome in some patients would give NOX66 an enormous edge in the race to finding a way of achieving this rare phenomenon and making radiotherapy potentially more curative even for late-stage cancer.

The first step in this process is to establish clinical benefit in one cancer type, and we believe that our quickest and surest path to market is via use of NOX66 in late-stage prostate cancer. Hence the DARRT-1 study.

In the meantime, we are pursuing 3 other potential applications (DARRT in wider cancer types, the LuPIN program, the CEP program), none of which at this time we are intending to take past Phase 2 level. The immediate purpose of these other clinical studies is to generate clinical data that will be used to support extended off-label (i.e. use in other cancers) use of NOX66 beyond an approved use in prostate cancer patients. We then have the option of running registration studies should we so wish.

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In terms of timelines:

  1. DARRT-1 Study

DARRT-1 has been designed to answer 2 key questions:

  1. What is the best dosage of NOX66? Is it 400mg, 800 mg or 1200 mg? We think 800 mg is our therapeutic dose, but the question still needs to be asked.
  2. What is the clinical outcome that will inform the design of the registration study? Is it going to be a direct response (better shrinkage of irradiated lesions), or an abscopal response (partial or complete) in some patients, or will it be a better symptomatic (e.g. less pain) response?

This study is underway. 24 patients are to be treated with NOX66 and the standard form of radiotherapy known as external beam radiotherapy. Each patient is on the study for 3 months (2-3 weeks’ treatment + scans at 6 and 12 weeks).

The key target milestones in this study are:

August 2018:   anticipated release of 6-week data from the first 12 patients and 12-week data from the first 4 patients.

Q3 2018:  complete recruitment of all 24 patients

Q1 2019:  completion of full study.

The Company is already preparing for potential success, with a planning meeting in the US in early-August with the medical oncologists and radiation oncologists from a range of leading US hospitals that have indicated an interest in being involved in the drug’s next stage of development. This meeting will review the DARRT-1 data and begin the process of advising on, and planning a multi-national registration study.

2. LuPIN Study

NOX sees this as a very exciting opportunity. It involves the use of NOX66 as a radio-enhancer in men with late-stage prostate cancer, where the radiation is being delivered intravenously via a radioactive antibody known as 177lutetium-PSMA-617 (Lu-PSMA).

In men with metastatic prostate cancer, secondary tumours can occur throughout the body, involving many of the bones in the skeleton plus different soft tissues (lymph nodes, lungs brain). It simply is not possible for externally delivered radiotherapy to reach such widely dispersed tumours, whereas an intravenously injected antibody (that targets prostate cancer cells) carrying a radioactive payload is able to.

Lu-PSMA has yet to be approved in any country, but nevertheless, the lack of any treatment options in late-stage prostate cancer means that Lu-PSMA treatment is beginning to be used increasingly in a number of countries. And with a potential 100,000+ men each year in developed countries being suitable candidates for PSMA therapy, it is a significant market opportunity. Close to 1000 men already have received Lu-PSMA treatment over the past couple of years, mainly in Australia and Germany, and the signs are that this will grow, right up until the time when we expect Lu-PSMA to receive marketing approval in 3-4 years.

If NOX66 can be shown to boost the response to Lu-PSMA treatment, then NOX66 is well placed to join the growing international roll-out of this drug.  That is the purpose of the LuPIN program….. to deliver proof of concept clinical data. What we are hoping to show is that NOX66 makes a big difference to Lu-PSMA therapy, shifting it from a modestly acting drug in about 50-60% of men, into a therapy that will work in most men and provide a deeper and longer-lasting response.  If we can demonstrate that, then that provides the opportunity for NOX66 to become a standard part of this new form of therapy.

LuPIN-1 is a 16-patient study being conducted by St Vincent’s Hospital, Sydney, for which Noxopharm is providing drug and financial support. Men with metastatic castrate-resistant prostate cancer are receiving up to monthly intravenous injections of Lu-PSMA in combination with NOX66. Patients continue to receive up to 6 treatments providing that their PSA levels continue to fall.

As announced on April 17 of this year, (http://www.noxopharm.com/irm/PDF/1550_1/StVincent39sHospitalstudypassesfirstmilestone)

a review of the early data provided justification to continue the study.

The anticipated key patient milestones in this study are:

July 2018: all initial cohort of 6 patients (400 mg NOX66) to have commenced treatment

August 2018:  first 4 patients complete treatment and cases reviewed

August 2018:  commencement of second cohort of 10 patients (800 mg NOX66)

January 2019: study closes.

The Company will be seeking to release study outcomes following each milestone.

With LuPIN-1 being run at just the 1 site, we now have decided to investigate accelerating the LuPIN program by running a parallel study involving upwards of 100 patients using multiple sites to ensure fast recruitment. That study would include a control arm.

3. Other studies

DARRT-2 will be a Phase 2 study across the full spectrum of solid cancers (with the exception of prostate cancer). The study will be multi-national and open to any patient presenting for palliative radiotherapy for metastatic cancer, which means we anticipate the subjects will range from the more common forms of cancer (e.g. lung, breast, large bowel) to the less common (e.g. ovarian, head and neck) to the rare (e.g. various forms of sarcoma).

The objectives are:

  • To provide a guide to the success of DARRT therapy in different cancer types
  • To provide the opportunity to gain Orphan Drug Status for success in rare cancers, potentially providing early market approval
  • To generate data that will be used to support the drug in the marketplace.

Protocol planning has commenced and has an objective of the study being opened in Q4 2018. This study will contain a control (no NOX66) arm so that we will have an objective measure of the benefit of DARRT therapy.

CEP-2  shortly is to be the subject of discussion by our medical advisors. The recent CEP-1 data pointed to the potential of using NOX66 to provide safer, and possibly more effective, chemotherapy. The next step is to take advice on what clinical approach oncologists and regulators (FDA, TGA, EMA etc) would see as the most beneficial way to use the CEP concept. I anticipate that the planning process covering protocol design, site selection and an IND application will take all of 6 months, meaning that CEP-2 (a Phase 2 study) will likely commence in Q1 2019.

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A cautionary tale

The recent release of the CEP study data brought out some interesting comments such as “you must be disappointed that the drug didn’t this work in every patient” and “having some patients die must mean that the drug failed”.

To start with, you can only test experimental anti-cancer drugs in patients who have run out of standard treatment options. On the whole these are patients who are close to the end of their lives. On top of their cancer with its damaging effect on the body, many of them have something called ‘comorbidity’ or other diseases such as those associated with advanced age (e.g. heart disease), while others are carrying the side-effects of therapy, having been through the mill of multiple rounds of chemotherapy and radiotherapy over many years. It is inevitable that a proportion of these patients will die from a variety of causes, even where the experimental drug might be working.

Then there are the patients who decide that they have had enough and choose to withdraw from the study, again, sometimes where the experimental drug might be working. There are certain commitments and obligations attached to being part of a clinical study, and for people who know they are facing end-of-life, those commitments can mean time away from family and that can be a difficult choice.

And finally, it is completely unrealistic to expect every type of cancer in every patient to respond to a particular treatment. Bear in mind that both recently approved ‘blockbuster’ immuno-oncology drugs (Opdivo, Keytruda) only work in about 10-25% of patients with certain types of cancer (e.g. lung cancer, melanoma, bladder cancer). They are even much less effective (<5%) in the common cancers such as prostate, breast and ovarian cancers. But even with this limited utility, global sales of Opdivo and Keytruda last year collectively were US$8.8 billion and growing.