Anti-TSLP therapy reduces inflammation in moderate to severe asthma
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Key takeaways:
- Patients with asthma saw a 23% reduction in FeNO with treatment.
- Most adverse events were mild, with no serious events.
- Three patients across both study groups developed anti-drug antibodies.
SAN DIEGO — A fragment antibody against thymic stromal lymphopoietin was safe and effective in reducing airway inflammation among patients with asthma, according to a presentation at the American Thoracic Society International Conference.
“Thymic stromal lymphopoietin (TSLP) is involved in chronic inflammatory disorders, including asthma and COPD,” Maria Belvisi, PhD, senior vice president and head of early research and development, respiratory and immunology, and Primal Kaur, MD, MBA, vice president and therapeutic area lead, inflammation, in global development, both of AstraZeneca, told Healio in a statement.
Tezepelumab (Tezspire; Amgen, AstraZeneca) is the first and only biologic that has demonstrated efficacy for a broad population of patients with severe asthma across phenotypes and irrespective of biomarker levels including bronchial epithelial cells, allergic status and fractional exhaled nitric oxide, Belvisi and Kaur continued.
“AZD8630/AMG 104, a novel molecule in co-development with Amgen, builds on the success of tezepelumab in severe asthma by targeting TSLP at the top of the inflammation cascade like tezepelumab,” they said.
Belvisi and Kaur called AZD8630/AMG 104 a first-in-class inhaled fragmented antibody.
“The small size of the molecule makes it suitable for development as an inhaled biologics therapy, which allows the medication to be delivered directly to the airway lining cells, where TSLP acts to trigger multiple inflammatory pathways,” Belvisi and Kaur said.
The drug’s delivery via inhaler also has the potential to expand its use to patients with unmet needs, Sarah Doffman, MBBS, executive medical director, early clinical development, AstraZeneca, also told Healio.
“There is a huge number of patients that don’t have access to systemic biologics,” Doffman said. “But going into more moderate disease when people are not eligible for a systemic biologic, this gives them the opportunity to get on top of the disease earlier.”
“The introduction of an inhaled biologic to asthma care would be a world first and represents a major scientific breakthrough, providing patients access to systemic biologics in a familiar format to inhaled standard of care that they are used to,” Belvisi and Kaur added.
Study design, results
The hybrid phase 1 study evaluated the safety, tolerability and pharmacokinetics of AZD8630/AMG 104 across different dose ranges in two parts.
In Part A, 104 healthy subjects received single and multiple ascending doses of AZD8630/AMG 104 from a dry powder inhaler once a day for up to 14 days.
In Part B, 77 patients with moderate to severe asthma and elevated FeNO who were treated with inhaled corticosteroids (ICS) and long-acting beta agonists (LABA) at baseline received 0.4 mg, 2 mg or 8 mg of the medication or a placebo once a day for 28 days.
The study examined lung function, which was a safety endpoint to ensure no decline in FEV1 over the treatment period, Belvisi and Kaur said.
“At the highest dose tested, we saw numerical improvements in lung function seen early in treatment and sustained to 28 days,” they said. “This correlates with the early effects seen on FeNO across all arms, with reductions seen by day 7, sustained to the end of treatment.”
Compared with placebo, patients treated with high doses of AZD8630/AMG 104 in Part B experienced a 23% reduction (P = .037) in FeNO, which the researchers called statistically significant.
After inhalation, absorption was classified as steady, and median times to maximum concentration ranged from 3 to 11 hours across the cohorts. The mean terminal half-life was approximately 21 to 37 hours across cohorts.
Also, doses were safe and well tolerated in Parts A and B alike, the researchers continued. Most of the adverse events were mild, the researchers added, and none were serious.
The subjects who were healthy and those who had asthma demonstrated linear and consistent pharmacokinetic results, the researchers added, supporting once-daily dosing.
One of the subjects in Part A, representing 1.3% of the 77 subjects receiving active treatment, developed anti-drug antibodies but did not report any associated treatment-emergent adverse events.
Two of the subjects in Part B, representing 3.9% of the 51 subjects receiving active treatment, developed anti-drug antibodies, but they did not report any associated treatment-emergent adverse events either.
“The rates of immunogenicity for this inhaled biologic seen in both healthy volunteers and patients were low and transient,” Belvisi and Kaur said.
Previous attempts to develop inhaled biologics for asthma treatment have been hindered by the development of anti-drug antibodies, they said.
“The prospect of a molecule that effectively reduces airway inflammation allied with low immunogenicity represents a potentially significant breakthrough in the treatment of moderate to severe asthma,” Belvisi and Kaur said.
Next steps
“We are excited about the AZD8630/AMG 104 phase 1 data, which demonstrates a significant and clinically meaningful reduction in exhaled nitric oxide and numerical improvement in lung function in moderate to severe asthma patients,” they continued.
Based on the significant reductions in airway inflammation among the patients with poorly controlled asthma and the overall safety profile, the researchers recommended further development of ASD8630/AMG 104 as an inhaled anti-TSLP.
“These data are really encouraging and have given us the confidence to move into phase 2. So that’s what our plan will be,” Doffman said.
“We hope that an inhaled biologic therapy may bring a much-needed innovative treatment option to patients with moderate to severe asthma who are currently uncontrolled, thereby broadening access to biologic therapy to those currently not eligible for systemic biologics,” Belvisi and Kaur said.
“The totality of the data is exciting, and we are evaluating next steps with our partner Amgen,” they said.