Science

Our New, Innovative Approach to treating Lung Cancer Cough

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Grounded in Evidence Driven by Innovation

Behind Biovara’s innovation lies a robust scientific foundation. Our lead product, LipAprep, is designed to address the complex neurological pathways that trigger lung cancer cough.

Here we aim to provide a clear and accessible overview of the clinical rationale, mechanism of action, and the compelling evidence that supports our approach. With links to peer-reviewed studies and insights from world-class clinicians, this section is a gateway into the science that underpins our mission.

1. The problem

Chronic Cough in Lung Cancer - A Significant Unmet Need

  • High Prevalence: Chronic cough is a widespread symptom among lung cancer patients, affecting over 80% at some stage of their disease. Chronic cough is the most commonly reported symptom of lung cancer.
  • Debilitating Impact: The cough significantly impacts various aspects of patients' lives, extending beyond just physical discomfort. Chronic coughing is known to impact physical, psychological, and social aspects of daily living, but in lung cancer, cough also contributes to pain, fatigue, dyspnoea, social isolation, 
and anxiety.
  • Persistence Despite Cancer Treatment: Despite advancements in anticancer therapies, cough often persists, indicating a separate underlying mechanism.
  • Impact on Palliative Care: Effective cough management is crucial for optimal palliative care, which has been shown to improve quality of life, mood, and even survival in patients with metastatic non-small cell lung cancer. Yet effective therapies to address the main symptom cluster in lung cancer—breathlessness, cough, and fatigue—are lacking.
  • Limitations of Current Treatments:
    Current approaches often involve treating underlying conditions or using general cough suppressants, which may not effectively target the specific mechanisms driving cough in lung cancer.
  • Broader Adverse Effects of Coughing:
    The physical act of coughing itself can lead to additional problems like sleep disturbances, vomiting, headaches, dizziness, muscle strains, and urinary incontinence.
2. The solution

LipAprep’s Novel Approach - Targeting the NK-1 Receptor

  • Differentiated Mechanism of Action: LipAprep offers a differentiated central and peripheral mechanism of action (MoA) for controlling lung cancer cough. This broader approach distinguishes LipAprep from most other products in development, which only target the peripheral MoA of cough (chronic cough and/or IPF cough).
  • Targeting the NK-1 Receptor: LipAprep is a neurokinin-1 receptor (NK-1R) antagonist. NK-1 receptors play a key role in controlling lung cancer cough.
  • Central and Peripheral Action: LipAprep targets NK-1 receptors both in the brain (centrally) and in the airways (peripherally). By targeting these receptors along the cough reflex arc, LipAprep has the potential to work independent of the initial cough trigger.
  • Role of Substance P: Substance P (SP), the natural ligand for NK-1 receptors, is released by sensory nerves in the airways, and its interaction with NK-1 receptors can trigger cough signals to the brain.
  • Peripheral NK-1 Receptors: Located on sensory nerve endings in the airways, they directly detect SP released from inflammatory cells or damaged tissue, leading to cough generation.
  • Central NK-1 Receptors: Found in the brainstem (nucleus tractus solitarius - NTS), where activation by SP can further amplify the cough reflex.
3. Targeting Lung Cancer Cough

LipAprep’s Mechanism of Action and Rationale

  • NK-1 Receptor Antagonist: LipAprep is a selective antagonist of the neurokinin 1 (NK-1) receptor, effectively blocking the actions of substance P (SP) in the body.
  • Blood-Brain Barrier Penetration: LipAprep exhibits the ability to penetrate the blood-brain barrier and occupy NK-1 receptors within the brain.
  • Emerging Role of SP/NK-1R in Cough: Evidence suggests a significant role for substance P and the NK-1 receptor in the complex mechanisms underlying the cough reflex. Animal studies show the influence of SP in the NTS and the inhibitory effects of NK-1 receptor blockade on cough mediated by vagal afferent C fibres.
  • Clinical Evidence in Lung Cancer:
    A small-scale clinical trial involving lung cancer patients who were experiencing chronic cough demonstrated that aprepitant, the active ingredient in LipAprep, has anti-tussive effects.

    This study showed a significant reduction in the frequency of coughing during waking hours, along with improvements reported by patients regarding the severity and impact of their cough. Mechanistically, the study showed that, in vitro, aprepitant inhibited the activation of vagal tissue by substance P.
  • Strong Rationale for Further Investigation: Based on the involvement of the SP/NK-1R pathway in cough and the positive preliminary clinical data, there is a strong rationale for further investigating aprepitant as a potential therapeutic intervention 
for this challenging condition.
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2.5 million people are diagnosed with lung cancer each year

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2.5 million people are diagnosed with lung cancer each year

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4. Pathophysiology

Understanding Chronic Cough in Lung Cancer

  • Multifactorial Mechanisms:
    Cough in lung cancer arises from a multitude of interconnected mechanisms.
  • Direct Tumour Effects:
    The physical presence of tumour tissue within the lungs can directly stimulate cough receptors located in the airways, triggering the cough reflex.
  • Inflammatory Responses:
    Inflammation caused by the cancer can elicit an inflammatory response within the body, and these inflammatory processes can stimulate the nerves in the airways, thereby contributing to the development of cough.
  • Pleural Effusion:
    Fluid accumulation in the pleural space can induce coughing.
  • Treatment-Related Cough:
    Paradoxically, the very treatments aimed at combating lung cancer can themselves lead to cough. Radiation therapy (causing lung scarring) and chemotherapy can both lead to cough.
  • Variable Cough Characteristics:
    The cough can range from a deep and chesty sound to a more subtle sensation resembling a tickle in the throat, and can be dry or productive, potentially evolving over time.
  • Co-occurring Conditions:
    Lung cancer patients may also have cough due to other conditions like asthma, COPD, GERD, or respiratory infections, necessitating comprehensive assessment.
  • Complexity and Need for Targeted Therapies:
    The multifaceted nature of lung cancer cough highlights the challenge of finding a universal treatment and suggests that understanding the predominant mechanisms in individual patients is key for targeted interventions like LipAprep.

Patient’s story

"My late father passed away as a result of lung cancer. As his condition deteriorated and his prognosis became increasingly bleak, the two defining symptoms were the constant pain (which was manageable) and his constant, debilitating cough (which was not).

The cough had a constant physical and psychological effect, and resulted in him being increasingly self-conscious, and ended up making him a virtual hermit. It certainly made his final years more painful and lonely. "

Alex Mackey

Patient’s story

"My cough is so bad that it often gives me really nasty chest pain. It keeps me up most nights and stops me doing many of the normal things I used to like to do.”

Stephen Jones
5. Lung Cancer Cough

The Role of the Substance P/NK-1 Receptor Pathway

  • Impact of Irritants (e.g., Cigarette Smoke): Exposure to irritants can increase SP synthesis, leading to augmented cough responses that can be blocked by NK-1R antagonists. This observation suggests that the substance P/NK-1 receptor pathway may be particularly relevant in lung cancer patients with a history of smoking.
  • Peripheral Sensory Nerve Activation:
    In vitro studies show that SP can directly depolarize vagal nerve tissue, indicating sensory nerve activation, and this effect is inhibited by an NK-1 receptor antagonist.

    This finding provides mechanistic evidence for a potential peripheral antitussive action of LipAprep, whereby it may reduce the sensitivity of sensory nerves in the airways that contribute to the cough reflex.

  • Pertinent Therapeutic Target:
    The evidence suggests that the SP/NK-1R pathway is crucial in mediating cough related to airway irritation and inflammation in lung cancer, making it a relevant target for LipAprep.
  • SP Release from Vagal C Fibres:
    Substance P is released from sensory nerve fibres in the respiratory tract (vagal airway C fibres), which are critical for the cough reflex.
  • NK-1 Receptor Activation:
    SP exerts its effects by activating NK-1 receptors in the central and peripheral nervous systems and other tissues, including potentially tumour cells.
  • Central Amplification of Cough:
    Activation of NK-1 receptors in the brainstem (NTS) enhances the cough reflex. Animal studies support this.
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Chronic Cough in Lung Cancer

Scientific References

Chronic Cough in Lung Cancer

Scientific References

6. LipAprep’s Action

Potential targets

  • Central Nervous System (Brainstem - NTS):
    LipAprep's ability to cross the blood-brain barrier allows it to block SP binding to NK-1 receptors in the cough reflex centre, potentially modulating afferent cough signals that trigger the cough reflex.
  • Peripheral Nervous System (Airways): Preclinical studies indicate a peripheral antitussive mechanism where LipAprep can inhibit the activation of vagal nerve endings by SP. The inhibition of SP-induced depolarization in vagus nerve tissue supports this. This suggests that LipAprep might not only dampen the central processing of cough signals but also reduce the sensitivity of cough receptors located in the airways.
  • Advantage of Dual Mechanism:
    The potential for both central and peripheral action could be particularly beneficial in treating the complex and multifactorial chronic cough in lung cancer patients.