While the entire US is facing an opioid abuse crisis costing thousands of lives and billions in healthcare costs, only a handful of drug research companies have been working overtime to develop alternative, non-addictive chronic pain therapies. Most of them are relatively small biotech companies devoted to translational research. Seattle-based Kineta, which has a strong heritage in immunology and in inflammation, believes its unique approach to developing a non-addictive pain drug which does more than just mask pain but may actually be disease-modifying can make an important contribution in fighting the opioid epidemic. Its perseverance in the lab has recently received a vote of confidence with the inking of a potential $359 million research agreement with biotech giant Genentech to further develop its chronic pain program.

Leading Kineta is CEO  Dr. Shawn Iadonato. Prior to co- founding Kineta, Iadonato co-founded and served as CSO of Illumigen Biosciences, Inc., where he led the successful discovery and preclinical development of the company’s anti-hepatitis C drug, which ultimately led to the sale of the Illumigen in December 2007 to Cubist Pharmaceuticals (now part of Merck & Co.). Before Illumigen, Iadonato managed the Human Genome Center at the University of Washington.

As part of a new industry series, WuXi AppTec Communications asked Iadonato his thoughts on Kineta’s chronic pain research, its potential, and what new developments are on the horizon for this new, non-addictive therapeutic avenue for managing chronic pain.

WuXi: Why has the drug industry been slow in developing effective alternatives to opioid pain medicines?

Shawn Iadonato: Unfortunately, there are a relatively small number of companies developing pain therapies and many are exiting the space altogether. There are likely a couple of the reasons. First, demonstrating efficacy in clinical trials for patients suffering from chronic pain is challenging. There is a high placebo effect that is often shown in these trials which can make it more difficult to truly demonstrate the effect of a drug.  Since many of the outcomes are self-reported measures, variability in responses can be high and difficult to show a significant difference relative to the placebo or a comparative drug.  Second, the commercial market is becoming more challenging. Many of the pain therapies on the market are generically available for pennies a day. That makes securing reimbursement for a new branded therapy a challenge for payers. They require seeing demonstrated clinical differentiation and/or better safety profile compared to the standard of care and lower cost generics. I believe that has resulted in fewer companies developing novel new pain therapies.

I believe there is still a tremendous opportunity to develop a novel therapy for chronic pain that can succeed in the market.  It will need to be differentiated and offer a better efficacy and safety profile than currently available drugs on the market and in development.

WuXi: Should there be more incentives for companies to develop non-addictive pain therapies? If so, what would you suggest?

Shawn Iadonato: Unfortunately, the opioid crisis has become a national epidemic and emergency.  I do believe that additional incentives need to be put in place to accelerate novel therapies to come to market.  The National Institutes for Health or other government agencies could easily increase funding to those companies developing non-opioid pain therapies which would encourage more companies and researchers to do so. The government has done the same during previous health crises.

Additionally, policies to provide drug development incentives similar to those already in place for rare disease therapies could be implemented. This could include R&D tax credits, subsidies, extended market exclusivity, and enhanced regulatory review. The FDA could offer breakthrough designation to accelerate the FDA approval process and waive user fees for novel non-opioids to treat patients with chronic pain.  These incentives have successfully accelerated the development of therapies for rare diseases as now have access to life changing medicines.

Biopharmaceutical companies developing novel non-opioid therapies are one piece of the solution.  However, it will take a multi-faceted effort to completely address the current opioid epidemic that our country currently faces.

WuXi: What spurred your company to enter this field?

Shawn Iadonato: Kineta has broad experience in immunology and inflammation which is a good fit with this drug target.  What drew us to the program initially was the opportunity to develop an asset with disease-modifying ability in pain.  Pain is not really considered a disease, it’s considered a symptom of disease and most of the drugs that are used to treat pain, typically opioids, are really masking pain reception in the brain. The opportunity to work on a drug that does more than mask pain, that potentially has disease-modifying qualities or neuroprotective effects or anti-inflammatory effects was very exciting for us.

WuXi: What is your non-opioid pain drug technology and how are you applying it?

Iadonato: Kineta’s work targets a receptor on neurons around the body called the α9/α10 nicotinic acetylcholine receptor(nAChR).  Our α9/α10 nAChR antagonists are derived from the venom of the Conus regius, a small cone snail native to the Caribbean Sea.  Because the receptor is only found in the peripheral nervous system, not the brain and spinal cord, drugs that target it likely won’t have the same severe side effects as opioids.  We see this as an opportunity to block pain at the site of the injury, wherever that may be, without having potentially those addictive, tolerizing, altering qualities – effects on cognition and coordination of respiration that you see in opioids.  We don’t believe that the drugs will have the same tolerizing and additive issues as opioids. Kineta is developing a once weekly subcutaneous injectable to treat chronic pain conditions.

WuXi: How would you compare the effectiveness of your pain medications to opioid pain drugs?

Shawn Iadonato: Kineta‘s conopeptide α9/α10 nicotinic acetylcholine receptor (nAChR) antagonists are differentiated from opioids. They demonstrated analgesic properties in several pre-clinical animal models. But what truly differentiates them are the anti-inflammatory and neuro-protective effects that we’ve also seen in the studies. We believe that combination may offer a disease modifying therapy that can slow or hold the progression of chronic pain.

In some cases, chronic pain is felt because of a positive feedback loop between the brain and spinal cord which continues to signal pain long after the injury is gone.  It’s a concept called central sensitization.  We think that one of the potential mechanisms of action of targeting α9/α10 nAChR could be to prevent this central sensitization through this combination of different mechanistic effects. By targeting α9/α10 nAChR, we could potentially resolve the causal injury leading to pain before central sensitization becomes established rather than simply masking pain by blocking neurotransmitters.

Research to date indicates that the target is not expressed in the Central Nervous System (CNS) which means drugs targeting the α9/α10 nAChR might not have the same addictive and tolerizing characteristics seen with opioids.  In animals treated with our drug, we don’t see any of the typical things that we would see with opioids like alterations in behavior, cognition, motor coordination.  Our hope is that as we develop this drug, we will not have any brain-related or CNS-related side effects, including addiction and tolerance.

WuXi: How does your approach and differ from other technologies in this field?  What are your advantages?

Shawn Iadonato: As we scan of the landscape of therapies in development, the non-opioid pipeline is quite thin. Most of things that we have to treat pain, aside from opioids, are really just repurposed drugs – like repurposed antidepressants or different formulations of opioid therapy with additional safety features.

Unfortunately, there are a few non-opioid therapies being developed.  Kineta’s α9/α10 nAChR antagonist is differentiated by its novel mechanism of action. It is first in class.  Additionally, it may be disease modifying due to its anti-inflammatory and neuroprotective effects.  This could slow or halt the progression of chronic pain in patients.  This is differentiating from the gabapentinoids and other new therapies in development.

WuXi: What are the risks and side effects associated with your medicines?

Shawn Iadonato: Kineta’s approach has worked preclinically because the α9/α10 nAChR is largely believed to be expressed in the peripheral nervous system and not in the CNS.  However, we believe that due to this novel target the drug will not have any of the centrally mediated effects like tolerance, potential for addiction, and effects on respiration and cardiovascular function.  To date, we have not seen any side effects or toxicities that concern us.  However, we will continue to more fully interrogate the mechanism of action and evaluate potential side effects in clinical trials.

WuXi: Which pain indications will your technology be used in?

Shawn Iadonato: Kineta has tested the efficacy of its lead compounds in several different animal models of pain, including spinal nerve pain, chemotherapy-induced neuropathy, and diabetic neuropathy.  Since the α9/α10 nAChR drug target is found predominately in the peripheral nervous  system, we believe that the drug will be best to use in neuropathic pain indications. Of particular interest to Kineta is lower back pain where nerves are pinched or compressed and is often caused by spinal injury.    Additionally, chemotherapy induced neuropathic pain is another potentially attractive indication for our α9/α10 nAChR antagonists. These two indications that are of particular commercial interest as there are no or few other products currently indicated to treat these forms of chronic pain. We will work closely with our partner Genentech on further defining the mechanism action and ultimately defining the best indication for the drug.

WuXi: Should addictive opioid drugs be eliminated, or is there still a place for them in treatment of chronic pain? Is this a point missed in the national debate on this issue? Doctors need something to treat legitimate chronic pain.

Shawn Iadonato: The reality today is there are approximately 100 million people who suffer from chronic pain in the United States.  There is a tremendous unmet medical need.  I don’t think opioid drugs should or will be eliminated because they are effective therapies!  They work very well and are very much in demand because there are no effective alternatives.  Given the magnitude of the opioid crisis, I do believe this point is being overlooked in the national debate.  Until a new therapy is approved that is as effective and provides a better safety profile, opioids will continue to be used.  Kineta is working diligently to develop an alternative for patients who suffer from chronic pain.

WuXi: Can you tell me more about your collaboration with Genentech

Shawn Iadonato: Kineta has successfully advanced this program into pre-clinical studies, however we believe that working with a partner can accelerate the program.  We recently signed an exclusive option and licensing agreement with Genentech and will be collaborating around the drug target.  Kineta will be performing most of the development work over the next two years with Genentech doing some work around the mechanism of action.  Considering that this drug has a novel mechanism of action and the drug target is relatively new, Genentech is an ideal strategic partner for Kineta on this program as they are an innovative, science driven organization.

WuXi: What impact will your technology/new drug have on the health care system?  Will there be substantial cost savings?

Shawn Iadonato: Unfortunately, approximately 50 people die every day from prescription opioid overdose, which has a substantial cost to society.  A study recently published by Altarum analyzed the cost of the opioid crisis in additional healthcare expenses and lost productivity and found that the opioid epidemic has cost more than $1 trillion since 2001.   Furthermore, the projects that the epidemic will cost an additional $500 billion between 2017 and 2020 if the current mortality rate persists.

There is a tremendous medical need for an effective non-opioid pain therapy without the potential for addiction for patients who suffer from chronic pain. Since our technology is a non-opioid, early data suggest that it will not have the same tolerizing and addictive effects of the opioids currently available on the market.

Offering an alternative to opioid therapies currently used should have a significant impact on patient outcomes and costs.  We are currently utilizing substantial healthcare resources to treat patients with chronic pain.  However, the downstream costs of treating the effects of addiction and overdose are creating an unsustainable burden for patients, the healthcare system and the government.  Providing a safer and effective non-opioid therapy is certain to have a significant impact on the costs of healthcare.

WuXi: How soon will your therapy be available in the US market for patients to use?

Shawn Iadonato: Our plan is to advance IND enabling studies later this year and to initiate first in human Phase 1 studies in 2019.  We will need to complete a full clinical development plan by conducting Phase 2 and 3 studies.  If all of the clinical development goes as planned, we could potentially have this on the market within approximately five years.