Hydra Biosciences sees TRP Ion Channels as Pathway to Opioid Alternatives

Innovation That Matters

While sky-rocketing death tolls from opioid pain drug addiction in the US have dominated the headlines in recent years, only slim effort has been made to find the alternative, non-habit-forming pain-killers doctors need to treat chronic pain.

In fact, only a relative handful of firms have been researching non-addictive pain drugs. Only now, after a Presidential Commission report and Congressional action, has the need to incentivize new pain research been recognized. One biotech company that has already been developing novel drugs to treat pain without the deadly side effects of abusive use is Hydra Biosciences based in Cambridge, Mass.       

“Our science targets the same cellular pathways that other pain medications do, but instead of acting in the brain, like opioids, our compounds work by blocking the pain signals directly in the area where the pain is occurring,” says Russell Herndon, president and CEO of Hydra Biosciences.

Herndon came to Hydra with over 25 years of experience in the healthcare and biotechnology industries. He has held senior management positions at Genzyme Corporation and Antigenics Inc. At Antigenics, Herndon served as chief operating officer and president from November 2000 through December 2005. He was with Genzyme Corporation from 1989 through 2000 holding various management positions, including president of Genzyme Tissue Repair, senior vice president of Genzyme Tissue Repair, and vice president of regulatory affairs for Genzyme Corp. Herndon received a bachelor’s degree in biology from Barton College and is a graduate of the Management Development Program at Harvard Business School.

WuXi AppTec Communications, as part of a new industry series, recently interviewed Herndon about the clinical direction and goals of Hyrda Biosciences as well as what the future holds for research into pain medicine.

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

Russ Herndon: Regulatory hurdles have created a significant barrier for innovative approaches to treating pain.  The existing paradigm was developed based on centrally acting CNS depressive compounds that carry with them potential life-threatening side effects. This has caused the FDA and others to create a regulatory framework that requires all drug companies to produce the same information in support of their compounds even if the mechanism of action is so different that these concerns are not the same. Add to this the broad label indication requirements, like chronic pain and acute pain, as opposed to more specific labeling options, for example, chemotherapy therapy induced peripheral neuropathies, and you get an extremely complex and expensive drug development process.

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

Russ Herndon: The regulatory hurdles and past failures with other treatment modality focused on pain, have driven investment away from innovation in this space.  Small companies, like ours, find it very difficult, if at all possible, to acquire the investment necessary to prove the value of our approaches. This in a time where the Small Company is being looked to as the engine of innovation makes it even more challenging. The intensified government involvement with finding a cure for cancer, things like the Cancer Moon Shot and others, have driven significant investment into that space.  Look at the value that is being provided to patients by innovative products like CAR T and other IO approaches. This is because investors saw commercial value in the development of these drugs. The FDA followed suite and provided Fast Track Designation and other expedited approval approaches to cancer products to help bring these products to market faster. This has driven even more investment into these innovative approaches.  We need something similar for companies developing non-addictive pain therapies.

WuXi: What spurred your company to get into this field?

Russ Herndon: Hydra Biosciences has been studying Transient Receptor Potential (TRP) ion channels for many years.  Through our deep understanding of the biology of these channels we identified a unique opportunity and approach to treat chronic pain. TRPA1 is expressed in pain sensing neurons, where it serves as a sensor of damage and inflammation.  Activation of the channel causes pain behaviors in rodents and burning pain in people.  However, unlike sodium channels, inhibiting TRPA1 does not cause numbness.  This is because the channel is a modulator of cellular excitability but is not required for action potential generation. Simply put, TRPA1 acts as a rheostat in pain sensing neurons, dialing up or dialing down their activity without blocking their ability to fire as compared to novocaine which simply turns the neuron off.

TRPA1 is also a peripheral target. Even local delivery of a TRPA1 blocker can be analgesic, showing activity in the brain is not required.   These characteristics, and others, lead us to believe that modulating TRPA1 could be a useful approach to treating chronic pain. We launched a multi-year program to better understand the mechanism and to develop orally available small molecules that could be used to test this hypothesis. We are currently on track to begin a phase 1 human clinical trial with our lead compound in the third quarter of 2018.

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

Russ Herndon: We have developed orally active small molecule modulators of the TRPA1 ion channel. We believe that by decreasing the activity of the channel in pain sensing neurons that we can treat chronic pain such as, diabetic peripheral neuropathies, chemotherapy induced neuropathies as well as others.

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

Russ Herndon: Unlike opioids, our treatment is not required to interact with a target in the brain. It antagonizes a newer class of ion channel that are not voltage gated, which makes it different from the sodium, calcium and potassium channels being studied in this therapeutic area. Voltage gated channels modulators have struggled in development to date because they have lacked the selectivity needed to only hit the channel of interest and not produce off-target side effects.

Many pain causing agents, such as formalin and others are known to be TRPA1 agonists. We believe that this further supports why antagonizing this channel should result in a positive response in pain sensing neurons.

WuXi: Should addictive opioid drugs be eliminated, or is there still a place for them in treatment of chronic pain?

Russ Herndon: One very true statement about treating individuals in pain is that there is no “Magic Bullet.”  There is no one treatment that can be used for all cases of chronic pain.  Doctors need multiple options in their armamentarium so that they can identify the best treatment for that specific patient. There are thousands of individuals suffering from chronic pain where opioid treatment is currently the only option. This is a topic that is discussed less often than limiting the number of doses a patient receives for each prescription or increasing the number of beds in treatment centers throughout the US and even expanding the availability of naloxone, all of which are important, but it is also important not to forget the people who suffer every day with intractable pain.

WuXi: What are the major scientific and regulatory challenges you face in developing your technology?

Russ Herndon: Ion channels are notoriously difficult to drug.  Identifying small molecules with the appropriate solubility and potency, as well as selectivity is a challenge. We have been fortunate to have identified a number of molecules that exquisitely target and antagonize TRPA1 and that also have excellent pharmaceutical properties. These molecules will be important as we test the hypothesis that antagonizing TRPA1 in humans can decrease pain sensation.  Along with the newness of the target come the regulatory hurdles that are in place which do not support the development of innovative products.  As I discussed earlier, the current regulatory paradigm was put in place to study centrally acting compounds for chronic pain indications and so require a level of testing that may not be necessary. There are also labeling issues that require a sponsor to perform studies in multiple types of chronic pain. This is because the labeling is limited to board category rather than more identifiable subsets of patients or conditions.  Lastly, as with all pain treatments, the subjective tools that are used to measure pain in the clinic provides for the opportunity of a strong placebo effect which is a challenge that must be overcome.

WuXi: What challenges do you face in bringing your drugs to market?

Russ  Herndon: Some of the challenges that we, as a small company, face in this field include the significant investment required to complete the multiple large clinical trials in various chronic pain patient populations that are necessary to seek regulatory approval; the historically challenging placebo effect that has impacted the development of many pharmaceutical products that have been studied to treat pain; and the commercialization infrastructure that is required to reach a general patient population.

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