Veterinary Development of Substance P-Saporin (SP-SAP)

A quick update on the pursuit of conditional approval of SP-SAP to  treat bone cancer pain in dogs. The FDA has already approved Minor Use/Minor Species (MUMS) designation for the drug, providing extended market exclusivity to treat the >10,000 annual cases of canine bone cancer-related pain, and the ability to commercialize the drug as soon as conditional approval is given.  An unexpected delay has occurred with the CMC (Chemistry, Manufacturing, and Controls) portion of the Conditional Approval application.  The drug used in the veterinary studies was prepared in a facility approved for Phase I/II clinical trial use, but not for commercial release of an FDA-approved drug.  SP-SAP will need to be produced in a facility approved for commercial release of an FDA-approved veterinary drug.  This is proving to be a difficult task.  Many facilities are approved at this level, but will not produce a veterinary drug until it is approved as a human drug.  We will keep looking.

Given the FDA’s receptiveness to the drug, clinical studies are in the planning stages to evaluate its effectiveness in the almost 10 million cases of osteoarthritis in dogs, as well as chronic pain in cats.  With the proper funding/partner, these studies could begin now with the SP-SAP already produced.

The drug, Substance P-Saporin (SP-SAP), has demonstrated remarkable pivotal-study efficacy as viewed in this video of one of the canine patient participants in the pilot veterinary clinical trial (Otis Patient Video, <2 min). Based on the impact of SP-SAP on the observable level of pain in these companion animals, the Center for Veterinary Medicine (CVM) is encouraging a multi-center efficacy trial to gain rapid full-approval for SP-SAP. Contract Research Organizations (CRO’s) have been put in place to provide GMP manufacturing, packaging, and labeling of the drug. Four veterinary specialty hospitals across the U.S. have been identified and coordinated for the multi-center efficacy trial. The expected success in this trial will provide full approval for SP-SAP, putting relief from all chronic pain indications within reach for companion dogs. Pain would no longer be a life-threatening disease for family pets

Veterinary Development of Substance P-Saporin (SP-SAP)

A groundbreaking pain therapeutic is poised for conditional approval in 2015 to treat bone cancer pain in dogs. The FDA has already approved Minor Use/Minor Species (MUMS) designation for the drug, providing extended market exclusivity to treat the >10,000 annual cases of canine bone cancer-related pain, and the ability to commercialize the drug as soon as conditional approval is given. Given the FDA’s receptiveness to the drug, clinical studies are in the planning stages to evaluate its effectiveness in the almost 10 million cases of osteoarthritis in dogs, as well as chronic pain in cats.

The drug, Substance P-Saporin (SP-SAP), has demonstrated remarkable pivotal-study efficacy as viewed in this video of one of the canine patient participants in the pilot veterinary clinical trial (Otis Patient Video, <2 min). Based on the impact of SP-SAP on the observable level of pain in these companion animals, the Center for Veterinary Medicine (CVM) is encouraging a multi-center efficacy trial to gain rapid full-approval for SP-SAP. Contract Research Organizations (CRO’s) have been put in place to provide GMP manufacturing, packaging, and labeling of the drug. Four veterinary specialty hospitals across the U.S. have been identified and coordinated for the multi-center efficacy trial. The expected success in this trial will provide full approval for SP-SAP, putting relief from all chronic pain indications within reach for companion dogs. Pain would no longer be a life-threatening disease for family pets

Otis Gets His Wag Back!

Dog with bone cancer jumps for joy over new treatment that made him pain-free after one dose!

Otis, the golden retriever, was in his golden years when bone cancer pain threatened to shorten his life. As a participant in a clinical trial aimed at pet dogs, he was given a single treatment with a pain therapy called SP-SAP that was developed by Advanced Targeting Systems (ATS).

The story of Otis’s relief from cancer pain is well documented in a video accessible on the Veiove Animal Health website. “Otis Gets His Wag Back” shows Otis before treatment and after. It is clear from Otis’s body language and gait there is change for the better, while the tumor has doubled in size.

Bone cancer at advanced stages often leads to animals being euthanized for pain-related issues. There are better options. Pain shouldn’t be a life-threatening disease for your pet. SP-SAP prevents chronic pain signals from reaching the brain. The pet’s brain no longer knows it is in pain from the cancer, but can still feel normal acute pain that can be treated with traditional pain.

A study sponsored by ATS has promising results that were published in the November 2013 issue of the journal Anesthesiology. Pet dogs receiving SP-SAP displayed significantly less pain than dogs receiving traditional pain care, with no visible side effects and an improved quality of life.

With the hope of translating these results to humans, a clinical trial testing SP-SAP on terminal cancer patients has begun. Early results are promising, but additional patients are needed. See http://clinicaltrials.gov/show/NCT02036281 for more information.

SP-SAP Facts:

  • Permanent relief from cancer pain
  • Single injectable dose
  • Successfully tested in dogs
  • In human clinical trials

For more information, contact us here.

Cancer Pain Relief in Pet Dogs has Direct Translation into Human Chronic Pain Conditions

Based on the recent publication by: Brown DC, Agnello K. (2013) Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 119(5):1178-1185 and the October 2013 press release by the American Society of Anesthesiologists, “Man’s best friends’ chronic pain relieved with new treatment, study finds: Findings could be useful to human cancer patients.”

A single injection eased severe, chronic pain caused by late-stage bone cancer in dogs, according to a study in the November issue of Anesthesiology. Dogs with bone cancer that received a neurotoxin injection had significantly more pain relief than those that got standard care without the injection. “Dogs are part of the family and we do everything we can to relieve them of pain and discomfort when they are sick,” said Dorothy Cimino Brown, D.V.M., School of Veterinary Medicine, University of Pennsylvania, Philadelphia. “In addition to sharing emotional attachments with our dogs, humans share many of the same ailments our pets suffer when fighting cancer. By studying the positive pain relief this treatment afforded dogs, we are hopeful it may also be effective for humans.” The evolution of bone cancer pain in dogs parallels what occurs in humans, with the frequency and intensity of pain increasing over weeks and months. As the cancer advances, both canine and human patients experience life-altering pain, which greatly affects their daily activities and quality of life. The standard treatment for dogs with late-stage bone cancer can include opioids, steroids, and palliative radiation. All of these treatments can have negative side effects.

The owners of 70 dogs enrolled their pets in this study. Half the dogs received an injection of a neurotoxin, called substance P-saporin (SP-SAP), as well as standard care. The other half (i.e., the control group) received standard care without the neurotoxin injection. The average age of the dogs was between 8 and 9 years and their average weight was 90 pounds. Multiple breeds participated in the study, including: Rottweilers, Labrador Retrievers, Golden Retrievers and mixed breeds.

Neurotoxins are historically known for the disease they can cause, such as botulism, according to Dr. Brown. More recently, however, scientists have learned to harness properties of neurotoxins for positive uses. For example, Botox is used to eliminate wrinkles and SP-SAP is used to decrease pain. The SP portion of the neurotoxin works by attaching to a pain-transmitting nerve and then the “SAP” part gets inside the nerve and causes it to die.

Within six weeks of beginning the study, 74 percent (26) of the dogs in the control group needed to be “unblinded” (in other words, their status in the study revealed) and their pain relief regimen adjusted. This is compared to just 24 percent of the dogs (8) needing adjustment to pain relief regimen in the group that received SP-SAP treatment. This was a statistically significant difference.

Other study results included a 6 percent increase in pain severity scores for dogs in the control group, while the dogs in the SP-SAP group had no change in pain severity score. In addition, the dogs in the control group had an 8 percent increase in how pain interferes with their typical activities, while the SP-SAP dogs had a 5 percent improvement in this pain impact score. Finally, one dog in the control group responded with lessened lameness, while 6 dogs in the SP-SAP group became less lame. While these secondary study results were not statistically significant because they were only assessed two weeks after injection, they are promising.

“The overriding goal of this research is to identify breakthroughs in managing chronic pain in both people and dogs by taking advantage of the fact that pets, through the course of their natural lives, develop many of the same medical conditions causing chronic pain that develop in people,” said Dr. Brown. “Additionally we can ‘measure’ this pain in companion animals like we do in people, quantifying severity and impact on routine activities, mobility and sleep.”

The positive pain relieving effect that SP-SAP had was significant, according to the study. It both provides promising data for canine patients suffering from cancer and encourages further research into the use of SP-SAP for chronic pain control in humans.

Cover Article: FDA Gives Green Light to Human Clinical Trials for Cancer Pain

Contributed by Douglas A. Lappi, Ph.D., President/Chief Scientific Officer, Advanced Targeting Systems, San Diego, CA

Substance P-Saporin (SP-SAP), ATS’s patented conjugate being developed for cancer pain therapy, has attracted a considerable amount of attention recently. Back-to-back publications, a press release and editorial were featured in the November issue of the journal Anesthesiology.

The first article, by Wiese et al.,[1] described the FDA-required intrathecal SP-SAP safety study in the dog. The authors concluded that intrathecal 15-µg SP-SAP reduced dorsal, but not ventral, neurokinin 1 receptor-positive (NK1r, the receptor for substance P) neurons at the spinal level of delivery with minimal side effects, whereas 150-µg SP-SAP resulted in motor neuron toxicity. Immunohistochemistry using a new NK1r antibody was correlated with in situ hybridization, and showed equality of identification on NK1r-expressing neurons.

The second study was in dog cancer pain performed by Brown and Agnello [2] at the University of Pennsylvania that showed, as the title states, “Intrathecal substance P-saporin in the dog: efficacy in bone cancer pain.” Companion (pet) dogs were randomized into a group that was going through normal pain management and a group that was treated with normal pain management, but received SP-SAP. Owners were kept in consult and the primary endpoint was measured as when the owners requested more pain pharmaceutical (dog activity, pain scores, and videography data were also collected). There was a significant difference between the two groups: more dogs in the control group that did not receive SP-SAP (74%) required unblinding and adjustment in analgesic protocol or euthanasia within 6 weeks of randomization than dogs that were treated with SP-SAP (24%; P<0.001).

The editorial comment by Hayashida [3] discusses aspects of the NK1r approach. Substance P has long been known to be important in normal pain transmission, but in the late 90’s, its receptor in the spinal cord began to be implicated in pathological pain. Substance P antagonists did not provide relief in human trials, so, Hayashida asks, why then would elimination of NK1r–expressing spinal neurons work? It is suggested that blockade of only one type of receptor is not sufficient, because of all the other neurotransmitters of pain (CGRP and glutamate, for instance) that still function on the pathology-producing neurons. Of great importance is that removal of NK1r-positive neurons removes the pathology of chronic pain, but there are other cells functioning on the input of other transmitters that allow for continued perception of normal acute pain.

The Food and Drug Administration has now allowed the use of SP-SAP in clinical trial. The patient population will be terminal cancer patients in pain that is refractory to opioids, a needy population indeed. The clinical trial will occur at the University of Texas Southwestern Medical Center in Dallas, under the direction of Dr. Carl Noe of the Department of Anesthesiology and Pain Management and sponsored by Dr. Arthur Frankel of UTSW’s Simmons Comprehensive Cancer Center. Dr. Frankel is a leading expert in the use of targeted toxins in humans. As Dr. Hayashida states: “We are looking forward to results of this clinical study.”

Photo Credit: Scott Rogers, Joe Ghilardi, Patrick Mantyh (University of Minnesota)
Yellow staining for saporin after internalization of SP-SAP by this single spinal cord neuron. Photo Credit: S. Rogers, J. Ghilardi, P. Mantyh (University of Minnesota).

References:     (back to top)

  1. Wiese AJ, Rathbun M, Butt MT et al. Intrathecal substance P-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology. 2013;119:1163-1177.
  2. Brown DC, Agnello K. Intrathecal substance P-saporin in the dog: efficacy in bone cancer pain. Anesthesiology. 2013;119:1178-1185.
  3. Hayashida K. Substance P-saporin for bone cancer pain in dogs: can man’s best friend solve the lost in translation problem in analgesic development? Anesthesiology. 2013;119:999-1000.

$3 Million Award from National Cancer Institute

Advanced Targeting Systems, the company that pioneered the targeting of specific cell types to manipulate them for the treatment of diseases and for research into the function of biological systems, has been awarded $3 million from the National Cancer Institute (NCI). Representatives from the NCI stated that the Advanced Targeting Systems proposal was ranked #1 for funding out of a nationwide program with hundreds of applicants. Advanced Targeting Systems will use the funds to advance its patented drug, SP-SAP, over the next two years to initiate clinical trials for cancer pain.

SP-SAP is a conjugate between the pain-processing peptide Substance P and the ribosome- inactivating protein saporin. The first publications of SP-SAP in the journal Science demonstrated a new direction for the understanding and treatment of pain pathology such as that which accompanies cancer. These have been followed by numerous publications from top- level scientists around the world delineating the activity of SP-SAP. The mechanism of action of SP-SAP is well characterized, a rarity in pain therapeutics: a small number of cells that process pathological pain signals are removed causing relief that appears to be permanent. Normal acute pain is unaffected.

The Food and Drug Administration has recommended that the first population to undergo treatment with SP-SAP is terminal cancer patients who are resistant to opioids such as morphine. Pain due to cancer is a great fear, at times greater than even the fear of death, in the progression of the disease. To make matters worse, many times this pain is unresponsive to the last stand treatment: opioids. There is also a common fear among terminal patients that current pain treatments will leave them unable to function normally at a time when it is personally extremely important for them. In preclinical tests, a single treatment with SP-SAP alleviated pathologic pain perception without affecting other sensory signal pathways.

Advanced Targeting Systems has assembled a team of experts to carry out the goals of the BRDG-SPAN project. Foremost among these are: Dr. Art Frankel from the Scott & White Cancer Research Center, Dr. Allen Burton from the MD Anderson Cancer Center, and Dr. Dorothy Brown of the University of Pennsylvania. All regulatory aspects of the project will be spear-headed by the professional team at Cato Research.

“I am gratified that the National Cancer Institute and the peer reviewers recognize the strength and quality of a ‘Dream Team’ of physicians, researchers and regulatory specialists that we have put together for this project,” stated Dr. Douglas Lappi, Principal Investigator and President/ Chief Scientific Officer of Advanced Targeting Systems.

About The BRDG-SPAN Program

The National Institutes of Health BRDG-SPAN Pilot Program (the Biomedical Research, Development, and Growth to Spur the Acceleration of New Technologies Pilot Program (RC3) is supported by funds provided to the NIH under the American Recovery & Reinvestment Act of 2009, a component of the Federal Stimulus Package. The purpose of this pilot program is to accelerate the transition of research innovations and technologies toward the development of products or services that will improve human health, help advance the mission of NIH and its Institutes and Centers (ICs), and create significant value and economic stimulus. The BRDG-SPAN pilot is intended to help address the funding gap, often called the “Valley of Death”, between innovative promising research and development (R&D) and transitioning those innovations to the market, by contributing to the critical funding needed by applicants to carry out later stage research activities and to pursue the next appropriate milestone(s) necessary to move a product/technology along a promising commercialization pathway. This program also aims to foster partnerships among a variety of research and development (R&D) collaborators.

About Advanced Targeting Systems (San Diego, CA)

Advanced Targeting Systems was founded in 1994 as a research reagent company. It has pioneered the use of Molecular Neurosurgery, the use of cell-specific targeting to Activate, Terminate or Stun cells for therapeutic or research purposes. The same principles are now being used by workers studying diabetes, immunology, cancer and other disease states.

About Scott & White Cancer Research Institute (Temple, TX)

The Scott & White Cancer Research Institute (CRI), a non-profit arm of Scott & White Healthcare, is designed to accelerate the development of new therapies for human diseases. Dr. Arthur Frankel heads CRI and is the leading expert on the use of targeted toxins in cancer, having served for more than 20 years in their clinical use.

About M.D. Anderson Cancer Center (Houston, TX)

M.D. Anderson Cancer Center has been selected by US News and World Report, again, as the leading hospital in the United States for cancer treatment. Dr. Allen Burton is Professor and Chair of the Department of Pain Medicine at M.D. Anderson Cancer Center with over 60 publications on cancer chronic pain. He has joined the team to assist in protocol design and to direct the Phase 1/2 clinical study. Dr Burton’s department saw over 10,000 patients last year for cancer related pain.

About Cato Research (HQ: Durham, NC with locations worldwide)

Cato Research is a full-service contract research organization with 20 years of experience. Their highly-qualified team offers integrated drug development services, including CMC, nonclinical, clinical and regulatory strategies as well as clinical trial support for drugs, biologics, diagnostics and medical devices.

Targeted Therapy for Chronic Pain

In 1997, SP-SAP (a chemical conjugate of Substance P and the ribosome-inactivating protein saporin) was created to eliminate Substance P receptor (SPR) neurons that propagate the signal for chronic pain. ATS has successfully completed preclinical studies, safety tests in animal models and a GLP toxicology study in rat, funded both internally and by the National Institute for Mental Health. In 2000, ATS was granted patent protection for SP-SAP. ATS is seeking an alliance to commercialize the therapeutic applications of Substance P-Saporin (SP-SAP), a large molecule, biochemical conjugate, that when delivered directly into the spinal fluid, seeks out and eliminates specific nerve cells that transmit chronic pain messages to the brain. Because of its size, this drug does not travel far from the site of administration. This innovative new treatment has created great excitement in the scientific and medical communities. This is an opportunity for an experienced drug company to participate in the developmentof a therapeutic with (1) no drug discovery required, (2) patent protection, (3) successful preclinical data, and (4) a defined initial target market with accelerated development timeline. SP-SAP preclinical data were the basis for two articles in Science and received international press coverage. The mechanism of SP-SAP is well understood. It enters SPR-positive neurons by internalization of the ligand-receptor complex. SAP enters the cytoplasm, enzymatically inactivates the ribosomes and shuts down protein synthesis, resulting in cell death. Four key points from these results are: (i) SP-SAP greatly reduces neuropathic and inflammatory pain, (ii) normal pain transmission is completely retained, (iii) pain relief appears permanent with no collateral pain states, and (iv) pain that occurs after treatment with SP-SAP can still be treated with morphine. The chronic pain population is one ofthe most pressing healthcare issues in the world, with an estimated size of 50-100 million persons in the U.S. alone. Chronic pain disables more people than cancer or heart disease and costs the American public more than both diseases combined—estimated at upwards of $40B in medical expenses annually. Advanced Targeting Systems is seeking analliance with an established pharmaceutical or biotechnology corporation in order to transfer SP-SAP into a working environment that can quickly and efficiently take the drug to human clinical trials and on to market. With the proper infrastructure SP-SAP could be in clinical trials in one year. Income from sales of the drug would be possible in three years. ATS is working with leading universities, has assembled a stellar advisory board, and industry-leading cancer clinicians are waiting to participate in clinical trials. The right alliance would be beneficial not only to the corporations involved, but to the millions who suffer from chronic pain.

SP-SAP Drug Development Update

Substance P-Saporin (SP-SAP) is a drug candidate that eliminates the spinal cord neurons that send the chronic pain signal to the brain. SP-SAP has been tested in a variety of animal models and proven effective in permanently eliminating the perception of chronic pain. ATS has completed extensive preclinical studies, a GLP toxicology study, and a safety study. SP-SAP is currently being used in a veterinary trial in companion dogs who are suffering from bone cancer. We are hopeful that treatment with SP-SAP will allow for the reduction of opioid administration and restore a better quality of life to these beloved pets.

The ultimate goal is to have SP-SAP approved as a chronic pain drug for humans. ATS plans to meet with the FDA in the next few months to see what final steps are necessary to begin clinical trials. This meeting will determine any additional testing that is needed and will outline the parameters of patient participation and monitoring in a clinical trial. The FDA has recommended that the first population of patients be terminal cancer patients who are non-responsive to opioid treatment. These needy patients currently have no options for pain relief and are being sedated as the only recourse. It is our deepest hope that SP-SAP will allow these patients to be restored to a better quality of life in their last few months to share precious moments with their loved ones. We will continue to keep our website updated on this drug development process.

Chronic Pain Drug – Update on SP-SAP Development

ATS continues to make progress toward human clinical trials with SP-SAP. Thanks to the financial support of the National Institutes of Health, National Institute of Mental Health, preclinical studies have been completed, protocols for drug production have been written and the first of two toxicology studies is done. This first study is a GLP toxicology study done in rat. At the time of this printing, the reports are being finalized with the results. The important preclinical work that was published in the journal Science was done in rat, but the studies were not GLP, nor did they examine enough parameters to meet the standards set for a toxicology study. The FDA requires one additional toxicology study be completed in another animal model before tests can begin in humans.

Another important part of the drug development process is the careful formulation of the drug itself. ATS is fortunate to have established a relationship with Dr. Arthur Frankel and his team at Scott and White Memorial Hospital, Cancer Research Institute in Temple, Texas. Dr. Frankel has supervised the production of four drugs under GMP (Good Manufacturing Practices) conditions. He is an expert in the field of recombinant toxin drug development. His group is currently working with ATS to improve the production of recombinant saporin (the toxic component of SP-SAP).

For several years ATS has been discussing the possibility of using SP-SAP in veterinary applications, in particular for bone cancer in dogs. Within the next few weeks, the protocol should be completed and the trial set to begin. SP-SAP is expected to provide relief from the debilitating pain these pets endure. With that relief they should experience a greater freedom of movement and enjoyment of life. Check the next issue of Targeting Trends for more details on this exciting project.

And, finally, here is a follow up on the July 2005 article regarding a partnering opportunity for ATS. Meetings have been held with potential candidates, but no deals have been finalized to form a partnership to bring SP-SAP to market for patients in chronic pain. ATS is looking for an experienced pharmaceutical or biotechnology company that can quickly take SP-SAP through the regulatory and clinical phases of development. If you have a connection with such a company, please contact Denise Higgins, Vice President of Business Development. ATS will provide a business plan and other pertinent
information to potential partners.

SP-SAP: How It’s Different From Substance P Antagonists

As most of you know, SP-SAP is a potential therapeutic that ATS is developing for use in the elimination of chronic pain. For the past seven years, preclinical studies have been carried out in the rat, safety and dosing studies completed in the dog and the first of two toxicology studies has begun in the rat. The second study is due to start later this year.

SP-SAP is a conjugate of the peptide, Substance P, and the ribosome-inactivating protein, saporin. It has been shown in all the recognized animal models of pain to eliminate the chronic pain signal. The acute (normal) pain signal remains intact. The removal of the chronic pain signal is permanent with no discernible side effects.

SP-SAP works by specifically removing the neurons in the spinal cord that express the Substance P (NK-1) receptor. This represents about 5% of the population of neurons in that area. Administration is through intrathecal injection, similar to the epidural used in childbirth.

spsap_05q2

Years ago, when the role of substance P in the transmission of the signal for pain became clear, it was immediately proposed by pharmaceutical scientists to construct analogs of substance P that would block the ability of it to bind to its receptor (see illustration). It was hypothesized that these antagonists would bring about pain relief. However, these analogs have always been disappointing. The reason for this may be that the pain pathway is very important and there are several redundancies; there are several other neurotransmitters, both peptides such as somatostatin or CGRP and smaller molecules such as glutamate, that are involved in transmission of the signal. Hence, blocking one of them is not sufficient; the others step in and take their place.

ATS is actively meeting with pharmaceutical companies to select the right partner to bring SP-SAP to market. There is a great unmet need among people throughout the world who are suffering from chronic pain. SP-SAP could bring these people a better quality of life. With the right partner, SP-SAP could be in clinical trial in a year.