Webinar hosted on Mar 29th, 2022 - Download Slides
Sherin Al-Safadi - Vice President, Medical Affairs (POINT Biopharma)
Good morning, good afternoon, and good evening everyone! Welcome to the second installment of POINT's Webinar Series. My name is Sherin Al-Safadi, and I'm part of Medical Affairs as Vice President of Medical Affairs, and I'd like to welcome you all and thank you very much for taking the time from your busy schedule today on behalf of the team at POINT.
So today's focus is going to be on dosimetry, specifically dosimetry for radiopharmaceuticals, and we have a guest speaker with us today who I will introduce very shortly, Dr. Ana Kiess, who will walk you through sort of the dosimetry 101; why dosimetry is important, and how it's measured specifically to oncology.
And so Dr. Kiess will present for about 30 minutes, and then with us as well today is Jessica Jensen who is our Executive Vice President of Clinical Development, and Jessica is going to walk you through the dosimetry results, a recap of the dosimetry results, that were recently presented at a congress from our SPLASH trial, our phase 3 trial in metastatic castration resistant prostate cancer.
So these are the customary forward-looking statements as you know we are a public company listed as PNT on the NASDAQ.
So just before I introduce Dr. Kiess, I want to take a moment to highlight POINT. We firmly believe as a company that the next pillar in the field of oncology and treatment is really going to be radiopharmaceuticals. We have a rapidly growing pipeline with early-stage and late-stage assets that focus across a different range of tumor types. We have 100% owned manufacturing infrastructure, and this is really critical because it helps us overcome a lot of the commercialization barriers that are traditionally associated with radiopharmaceuticals, and this is really important for us in an effort to make sure that we can get these therapies to the bedside of patients across the world.
The team is highly experienced in radiopharmaceuticals, we're very much driven by the company's mission and vision, and at present the core focus is on creating this platform for these radiopharmaceuticals that are truly going to be next-generation in terms of these emerging therapies.
So today's focus is going to be on radiation dosimetry, as I mentioned. What it is, how it works, this is a really powerful tool that's used to estimate the safety of a radiopharmaceutical total dose, and Dr. Ana Kiess is going to walk us through that in more depth.
So I'd like to take this opportunity to give a big welcome to our guest speaker Dr. Ana Kiess, who is an Assistant Professor of Radiation Oncology and Molecular Radiation Sciences at John Hopkins Hospital. Dr. Kiess has a clinical practice and a research focus very much on radiopharmaceuticals both from the perspective of imaging, and also for treatment or theranostics, so she's combined both in her clinical practice and we're very excited to welcome her. So without further ado, I will pass it on to Dr. Kiess.
Dr. Ana Kiess, M.D., Ph.D. - Assistant Professor of Radiation Oncology and Molecular Radiation Sciences (Johns Hopkins Hospital)
Thank you very much for the kind introduction. It's my pleasure today to join you and to present on this important and interesting topic. I receive clinical trial funding from these pharmaceutical companies but I'm not compensated in any way for this webinar today. Today I'd like to give a broad overview of dosimetry, its importance, how it is performed, how we interpret it and the limitations on our current interpretation, and the exciting future directions for the field of dosimetry.
So first, what is dosimetry? This refers to the measurement, calculation, and assessment of absorbed dose to tumors and normal tissues it is most developed in external beam radiotherapy, such as shown on the right, which is x-rays given by a linear accelerator, and in external beam radiation we actually prescribe to absorb dose, so is on the image in the far right you see a patient with the pelvic bone metastasis and the dose of 30 gray (Gy) is prescribed to the target volume.
Absorbed dose is in energy density of gray (Gy), which is joules per kilogram absorbed, and that directly results in DNA damage that causes the tissue effects of radiation. Now for radiopharmaceutical therapies we often refer to the activity or amount of radionuclide in a particular energy state, and particularly the administered activity given to the patient, such as what is in the vial of lutetium PSMA on the left. We can also calculate absorbed dose and project it on a 3D image, like the CAT scan shown on the right, in gray.
Why is dosimetry important for radiopharmaceutical therapies? In phase 1 trials, it aids in dose selection, it is also predictive of toxicities and tumor response and has the potential to be used for personalized medicine. Here's an important example of tumor dose response for PSMA targeted therapies, from the group in Australia who observed a correlation between the tumor dose and PSA response in men with metastatic castrate resistant prostate cancer. So they had to segment out on the image on the left the tumors throughout the body, in order to calculate the absorbed dose to the tumors, and in the graph on the right we see that the patients were much more likely to have a PSA response after 12 weeks when they had a higher absorbed dose to the tumors.
Importantly they also observed a relationship between the dose to the tumor and that goes to the normal tissues and the total volume of disease. So patients had a higher tumor burden, had lower doses to the parotid and kidneys, which leads to potential for altering or custom fractionating the radiation for different patients with different volume of disease in the future.
How do we perform dosimetry? We must collect data typically images to reconstruct the underlying pharmacokinetics. So for pharmaceutical therapies, pharmacokinetics refers to the absorption of a drug if it's oral into the bloodstream, and the distribution from the bloodstream to the tissues, followed by metabolism of the drug and excretion through the kidney and or liver. So the plasma concentration of the drug drops very rapidly during the distribution phase as it is distributed to tissues, and the tissue concentration rises through the distribution phase and then lowers through metabolism and excretion.
How do we measure the plasma and tissue activity? So for radiopharmaceuticals the plasma activity can be measured directly using a gamma counter from the blood samples at different time points. The tissue activity is more difficult to measure but with radiopharmaceuticals you can measure it pre-clinically by ex-vivo tissue sampling of the different organs, and measuring the percent injected dose per gram, again using a gamma counter.
Clinically we measure using imaging, gamma whole body scans or SPECT CT at different time points, and this is a patient of mine who receives lutetium PSMA therapy, and showing the uptake of drug one hour post treatment, four hours, 24 hours, and 48 hours. In for example the 24 hour image you can see the uptake in the bone metastases in the right shoulder and spine, and then the clearance of drug through excretion through the kidneys and in the bladder.
So modern dosimetry is performed using quantitative 3D SPECT CT imaging, which has been developed significantly over the past several decades. This type of imaging detects single photons or gamma rays of different energies emitted from the drug at various locations throughout the body, and there are many detectors that receive the photons, and then there's reconstruction into 3D images. So there's technical challenges at institutions and across inter-institutional comparisons, of standardizing the calibration and reconstruction of SPECT CT images. And I want to acknowledge Stephen Graves, a medical physicist collaborator at University of Iowa, for several of these images as well as my colleague Rob Hobbs.
Once you have the images, the actual absorbed dose is calculated by one of two different methods. The first method is simpler, and it's activity based using the published phantom derived S values from the MIRD pamphlets, and the second method is using dose rate and calculating using Monte Carlo calculations and patient-specific anatomy, and that is the gold standard. Both of these methods though use imaging at multiple time points via SPECT or gamma camera imaging.
So this is showing the activity based method where you have your images at different time points and you integrate the time activity curve, and then you use the activity maps in conjunction with the phantom derived S values from MIRD pamphlets, to calculate absorbed dose.
The second method, or the dose rate based method, uses 3D dose rate images, and integrate the dose rate over time directly to get voxelized dosimetry values, and their advantage of this because it's not dependent on the sort of phantom model of human anatomy, and you get much more detailed 3D results, and you're able to also calculate tumor dosimetry which is not incorporated into the MIRD pamphlet model. Also is very useful for further study of radiobiology and bioeffect modeling and scientific analyses.
Historically dosimetry has been using an endpoint of mean dose to the whole organ or tumor, however more advanced dosimetry is possible in 3D and can result in a dose volume histogram but we have to always keep in mind that this is limited inherently by the spatial resolution of SPECT CT imaging.
Now the trickiest question is how do we interpret dosimetry? And this depends on the tissue or organ that you're interpreting and it can depend on the potential for acute or late toxicity in that given tissue, and the potential for repair of toxicity, or repair of DNA damage. It depends on which radioligand, which affects the distribution of the drug, and which radionuclide we're using, particularly if it's an alpha versus a beta emitting radionuclide.
So where do the current FDA absorbed dose limits come from? They mostly come from the external beam radiation data, and particularly this large analysis of quantitative analyses of normal tissue effects in the clinic, that was initially published in 2010 in the red journal, which is radiation oncology biology and physics, and that was based on review of literature and meta-analysis from many decades of experience with external beam radiation.
Some of the toxicities that are relevant to PSMA targeted therapy are going to be addressed next. So radiation induced xerostomia, or dry mouth, is related to dose to the salivary glands, and it is a potential concern because there's PSMA expression on the surface of salivary acinar cells. This is a slide from Hopkins of a normal parotid gland showing PSMA expression in brown at the surface of the parotid gland cells.
From QUANTEC, from external beam radiation, with external beam radiation we limit the mean parotid dose to less than 25 gray, to yield a less than 20% chance of long-term salivary function of less than 25%. The acute side effect of dry mouth is related to cell membrane damage and impaired signaling, whereas the potential for late dry mouth or chronic dry mouth is related to death of the progenitor cells that limits regeneration. When dry mouth is severe it can cause dental caries, difficulty swallowing, changes in speech, and very much affects quality of life, but it does improve gradually over six to 24 months, as shown in this graph on the right. There's pieces from patients with head and neck cancer you have a high dose on the ipsilateral side of the parotid and the lower dose on the contralateral gland, you get a little bit of recovery over time in the ipsilateral parotid, and a lot of recovery and compensation and the contralateral product function over time after exposure. This is time after exposure to the radiation, and dry mouth is more likely in older patients than with repeated doses.
So through the lens of external beam radiation we can try to interpret some of the data that we have on salivary doses for PSMA targeted therapies, but they as we'll see in a moment the interpretation is quite limited still. The same general mechanism is likely in effect for radiation-induced dry eye, or xerophthalmia, related to PSMA expression the lacrimal glands. Radiation induced dry eye can cause discomfort and visual disturbance, particularly blurry vision, and the mean lacrimal dose of less than 25 Gy for external beam radiation results in a less than 13% risk of grade 2 toxicity.
Now radiation-induced nephrotoxicity, or kidney damage, is a concern because of PSMA expression in the proximal renal tubule cells, as well as vascular cells. And this is an image from a paper we published on PSMA targeted alpha emitter therapy. This is an alpha camera image of a kidney one hour after administration of a PSMA targeted alpha therapy. As you can see these tiny little dots of uptake are in the proximal renal tubules, it's not homogeneous distribution at all, whereas the external beam radiation data is related to the dose to a more homogeneous portion of the kidney, so a dose of less than 23 Gy to a third of the kidney yields less than 5% risk of chronic kidney injury. This dose limit is from QUANTEC IJROBP 2010, but the FDA may refer to the original Emami IJROBP 1991 tolerance dose of less than 23 Gy mean to the whole kidney yielding <5% risk of injury within 5 years.
Now in contrast to dry mouth or dry eye, there is rarely acute symptoms or short-term side effects of radiation-induced kidney damage, it often presents later and chronic injury typically greater than 18 months later is characterized by hypertension, elevated creatinine anemia, or renal failure. But if there's been no changes in the lab value of glomerular filtration rate by two years, there will likely be no toxicity at all, and this is something that's important in interpreting the data for potential renal toxicity.
There's also often referred to concerns for second primary malignancies after any radiation therapy. This has been observed after radioactive iodine for low-risk thyroid cancer, so patients who are long-term survivors of thyroid cancer that received radioactive iodine years earlier are at slightly higher risk of developing salivary gland malignancies. For salivary gland cancers overall the incidence ratio is 3.8 for patients who are exposed as an adult greater than 45 and even higher if they were exposed at a very young age for the incidence of salivary gland malignancies.
So there is a concern regarding applying external beam radiation data to radiopharmaceutical therapies because there are many additional variables in the bio-effect modeling of the radiation dosimetry for radiopharmaceuticals. So there's molecular targeting of the radiation that results in a non-uniform tissue dose distribution, there's also much shorter range of the radiation, so the distance that the radiation penetrates, and there's variability in the biologic effectiveness of the radioisotopes, particularly higher for alpha emitters, and the rate of the dose is low and variable for radiopharmaceutical therapy.
So just in a table format, radiopharmaceuticals versus external beam radiation.
For radiopharmaceuticals you have a long exposure of a low dose rate, compared to external beam where you have a short exposure of a high dose rate, and then the range is only millimeters for beta emitters or micrometers for alpha emitters, whereas for photon the range is in meters. As we saw on the earlier dose distribution maps, it can be a much more homogeneous dose distribution with external beam than radiopharmaceuticals, and the linear energy transfer and relative biologic effectiveness are variable for radiopharmaceuticals.
So the biologic effect or RBE for alpha emitters is particularly high both for normal tissues and for tumors, which results in a greater anti-tumor efficacy. They also have very short range so there was less marrow toxicity seen in early studies of actinium-225 PSMA targeted therapy due to that short range, and you can seethe sharp decline in PSA seen with alpha emitters.
However, there was also dose limiting xerostomia, or dry mouth, observed at doses greater than 100 kBq/kg/cycle with alpha emitters greater than what was observed with beta emitters. We want to highlight that the shorter range of the alpha emitters in the range of microns makes microdosimetry important.
So when we talk about dosimetry at the organ level, or at the tissue level like we saw for the kidney proximal tubules, for alpha emitters we actually need to look at dose at the cellular level which can influence the effects. So the dose of the cell membrane here in the image on the right versus the dose to the nucleus.
Other future directions for dosimetry include in combination with external beam radiation. We have this study called the RAVENS study open at Hopkins, combining stereotactic radiation with radium-223 systemic radiopharmaceutical therapy for hormone sensitive oligometastatic prostate cancer, and we combine those symmetry from the external beam radiation with dosimetry using advanced SPECT CT methods of the radium in a separate SBIR study.
In the future there's also the potential for personalized dosimetry. This study of yttrium-90 microspheres, so that if they use dose escalation using personalized dosimetry they were able to achieve a longer overall survival compared to patients who underwent standard dosimetry. You can prescribe to the tumor absorbed dose or normal tissue absorbed dose and possibly use that for dose escalation and other therapies. However there are some barriers to applying personalized dosimetry across the global scale, and even at any given institution to standardizing and having the capacity to do pre-treatment of symmetry on a per patient basis.
Another important future direction for the field of dosimetry is collecting data and collaboratively interpreting it. So we have organized a conference under the leadership of the medical physicist Dr. George Sgouros that will be held in Greece this fall, similar to QUANTEC for absorbed dose from external beam radiation, we are going to have RPT-TEC which is radiopharmaceutical therapy normal tissue effects in the clinic, to review the collective experience, relating relationships of toxicity and absorbed dose for radiopharmaceutical therapies. Our objective is to arrive at new normal organ toxicity avoidance doses expressed as two-grade equi-effective doses for radiopharmaceutical agents and particular radionuclide combinations.
So in conclusion, dosimetry is a really powerful tool for understanding and optimizing radiopharmaceuticals but we're still in the early phase of development both from a scientific standpoint and from a standardization and policy standpoint. We're likely under-dosing many radiopharmaceutical therapies with the current absorbed dose limits from QUANTEC, we need to data share data collect and have long-term follow-up to revise the absorbed dose limits, and this is why we've organized the RPT-TEC conference. There are many future directions scientifically that are under investigation including bioeffect modeling, combining therapies, advancing alpha dosimetry, and conducting microdosimetry to account for the spatial heterogeneity of the dose. And the holy grail of the potential for future personalized dosimetry and for using dosimetry for better patient selection. Thank you so much for your time and attention on this important topic and we welcome contact afterward with any questions.
Jessica Jensen - Executive Vice President, Clinical Development (POINT Biopharma)
Thank you Ana, that was an incredibly insightful presentation on a complex topic, but you you made it easy, and it's it's truly an honor to have you. For those who may not know or be aware, Ana is really advancing the field with many important contributions, especially initiatives in leading consensus efforts between academia, industry, and health authorities, which is really important to to really move the needle and transform the administration of these products. Hello to everyone who joins us online today. For those who don't know me, my name is Jessica Jensen, and I'm an Executive Vice President leading our Clinical Development programs at POINT.
We will now transition the discussion to POINT's lutetium-177 PSMA therapeutic program, and specifically recent data generated on our late stage asset, which Lu-PNT2002, from our SPLASH study. The SPLASH study is our Phase 3 program, however it starts with a lead-in cohort, and this data was recently released at the SNMMI mid-winter congress, and I'm pleased to provide a short recap here today.
As a reminder, PNT2002 is a PSMA-targeted therapy in development for men with metastatic Castration-Resistant Prostate Cancer, or mCRPC. And this is being studied in those men who have failed an androgen receptor axis targeted therapy, or ARAT, and have yet to receive chemotherapy for their mCRPC state of disease.
This remains a fatal state of a man's journey with prostate cancer, especially when evaluating such limited treatment options other than chemotherapy. And we've moved incredibly fast from a pre-IND meeting with FDA, to completion of enrollment in the lead-in phase, and initiation of the randomization phase in just under 1.5 years. All of these efforts are motivated by an urgency to drive transformative change for patients in the treatment paradigm you see presented on the slide.
You see here the SPLASH trial design with the lead-in phase highlighted on the left portion of this slide. As you recall Ana mentioned, one of the many advantages of dosimetry is its ability to aid in dose selection and predict toxicities. And that is exactly what this lead-in phase was designed to do. In fact, we incorporated pre-specified criteria into the protocol to determine if we should advance to the randomization phase with or without a change to our dosing regimen.
Another very nice aspect of this design is the lead-in phase was studied in the same population as intended for the randomization phase. With no change to the dose, patients receive up to a total of 27.2 GBq fractionated over 4 doses every 8 weeks.
Following the lead-in, we have designed a 2:1 randomization for patients to either receive Lu-PNT2002 with pre-specified best supportive care vs. a 2nd line ARAT switch, or in this case abiraterone or enzalutamide.
We have powered this study to evaluate radiologic progression free survival as the primary endpoint, and from what we know in the literature these men have been failing at approximately 4 months.
However, a unique opportunity for these SPLASH patients who fail in the control arm, is the option to receive the investigational agent after contributing their primary endpoint radiologic progression data. We believe this is an important element for the overall trial fidelity and will help with patient retention. So I now look forward to presenting to you the dosimetry data from the lead-in cohort of the study.
Before I proceed, I just want to make a special thanks to Dr. Beauregard for initially presenting this data at the mid-winter meeting from SNMMI. The radiation absorbed dose estimates that you see presented here were calculated with both whole-body planar and SPECT CT imaging following an initial dosing cycle based on 5 timepoints, for up to 7 days post dosing. As you see, we reveal our initially planned cumulative dose of 27.2 GBq is within or well below acceptable thresholds for minimizing the risk of radiation induced toxicity to these highlighted critical organs of interest, also previously highlighted by Ana.
We were very pleased to learn our kidney dose is predicted to result in less than 20 Gy after the intended full 4-cycle administration, which is on the low end of surrogate benchmarks, as Ana mentioned often defined as 23 Gy. But even more important perhaps is the red marrow radiation absorbed dose. As a very common and potentially fatal toxicity to patients in this class is myelosuppression or marrow toxicity. And we see here a favorable marrow radiation absorbed dose estimate of 0.92 Gy, or more than half of acceptable thresholds, defined as 2 Gy. This helps us expect lower overall marrow adverse events and may also enable later line administration of myelotoxic agents to patients, or perhaps, an area of interest to us, is the potential for combination opportunities.
I was also pleased with our lacrimal and salivary gland absorbed dose estimates.
As you may recall from Ana's presentation, the target threshold to limit xerostomia, or dry mouth, is less than 25 Gy and we're estimating only a mean 9.15 Gy dose. While these organs can pose challenges for accurate dosimetry due to their small size, we see our doses comparable to the literature and look forward to reporting our clinical toxicity data to these organs which may be even more enlightening later this year.
In summary, we were able to advance from the lead-in phase to the randomization phase based on all pre-specified criteria of safety and preliminary efficacy having been met in the lead-in phase of the SPLASH protocol. The FDA granted an approval to proceed earlier than anticipated, and we are now enrolling into the randomization phase with ongoing DSMB meetings, and no changes to the study designed to date. We have observed a low discontinuation rate due to adverse events and a lower overall rate of myelosuppression as compared to published safety data of similar ligands. Likewise our kidney dose was below acceptable thresholds and aligned with previously published data of comparable ligands. And ultimately we are eager to report on additional safety and efficacy data from this 27 patient lead-in during the second half of this year.
With that I've been asked now to conclude today's session, we thank you for joining as well as for your interest in our organization and the overall field, but most importantly we want to thank the patients who participate in the study to date, and the very large and awesome study teams across all our sites, internally here at POINT, and our partners. We are eager to further the field of radiopharmaceutical targeted therapy by advancing our next platform of next generation assets and sharing more about that in the near term, and we look forward to providing additional follow-up on this program and ultimately collaborating with you to enable the best possible outcomes, both clinically and based off of quality of life, for our patients. Thank you very much.