• Further validates company’s dual GPCR targeting approach

SEOUL, South Korea & California—GPCR Therapeutics, Inc., a clinical-stage, international biopharmaceutical company, is pleased to announce the publication in the esteemed scientific journal, Proceedings of the National Academy of Sciences (PNAS) that was spearheaded by Dr. Niña Caculitan, Director of Clinical Development.

This research underscores the company’s commitment to targeting diseases with cutting-edge approaches against GPCRs and discovering novel therapeutics. Detection of multimeric complexes by CXCR4 with other GPCRs in a live-cell environment validates the dual GPCR targeting hypothesis. The paper, authored in collaboration with Prof. Adam Smith, Associate Professor at Texas Tech University, is titled “The β2-adrenergic receptor associates with CXCR4 multimers in human cancer cells.”

Both CXCR4 and β2AR receptors play active roles in oncogenesis. The work uses time-resolved fluorescence spectroscopy to quantify CXCR4 and β2AR interactions as they form complexes in live cells under physiological conditions. Differential propensities of GPCRs to cluster in non-cancer versus cancer cell lines was observed, suggesting that GPCR multimerization is significantly affected by the plasma membrane environment. Furthermore, the ligand for β2AR, epinephrine, increases the CXCR4-β2AR heteromerization. Thus, antagonizing its binding could decrease heteromerization and may have therapeutic benefits that can be missed by targeting only CXCR4. This supports the development of new drugs to treat CXCR4-positive cancers using combination therapies.

Dr. Dong Seung Seen, Founder and CEO of GPCR Therapeutics based in Seoul, spoke about Dr. Caculitan’s accomplishments. “Dr. Caculitan represents the highest ideals that our entire team strive for. It is this level of understanding complex science that will lead us to success with the unique approach upon which our company was founded.”      

References:

(2024). The β2-adrenergic receptor associates with CXCR4 multimers in human cancer cells. Proceedings of the National Academy of Sciences, 121(14), e2304897121.

https://doi.org/10.1073/pnas.2304897121

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing therapeutics built on its proprietary GPCR data. GPCR Therapeutics has its HQ in Seoul and a subsidiary in the San Francisco Bay Area, USA. The company’s lead asset, GPC-100/Burixafor, targets CXCR4. GPCR has a US phase 2 trial of GPC-100, G-CSF and Propranolol, a beta blocker, for stem cell mobilization in multiple myeloma patients (NCT05561751). For more information, please visit gpcr.co.kr and follow us on LinkedIn.

Contacts

GPCR Therapeutics, Inc.

Jaehyuk Imm

+82-2-878-2848

jaehyuk.imm@gpcr.co.kr

Seoul, Korea, & Redwood City, California, 14 December 2023 – GPCR Therapeutics, Inc., a clinical-stage international biopharmaceutical company announces it enters into an out-licensing agreement with Bridge Biotherapeutics (KQ288330) for the CXCR4-LPA1 inhibitor combination method of treatment. GPCR receives upfront payment of KRW 2 billion (approx. USD 1.5 million), and a 50:50 profit-share on future commercialization, including sub-licenses.

Last September, GPCR published the paper on the direct interaction between two different GPCRs, CXCR4 and LPA1, in the peer-reviewed academic journal ‘Cell Communication and Signaling’(1). The target GPCRs are known to promote fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Through various in vitro experiments, the company found that the efficacy of LPA1 inhibition can be further maximized by inhibition of CXCR4, thereby securing a scientific basis that the CXCR4- LPA1 inhibitor combination may be necessary for full anti-fibrotic activity. Based on this finding, GPCR filed a provisional patent application on the CXCR4-LPA1 inhibitor combination method of treatment.

In collaboration with Bridge Biotherapeutics, GPCR will pursue joint development and commercialization of the combination therapy. Conducting a multinational phase 2a clinical trial of BBT-877, an autotaxin inhibitor for the treatment of IPF, Bridge Biotherapeutics has been accelerating development of its proprietary IPF pipeline.

Dr. Dong Seung Seen, founder and CEO of GPCR Therapeutics, commented, “Since the publication of our paper, various global companies have expressed interest in the relationship between LPA1 and CXCR4 and its inhibitory effect. Due to the versatility of our patent, we look forward to collaborating with many IPF-targeting companies, starting with Bridge Biotherapeutics.”

James Lee, founder and CEO of Bridge Biotherapeutics, said, ‘We are encouraged to collaborate with GPCR Therapeutics to uncover new possibilities of IPF treatment. Our collaboration will help us move forward to identifying and bringing novel treatment of IPF, such as a combination therapy of LPA1 and CXCR4 inhibitor, based on GPCR’s latest research.”

IPF is a progressive chronic lung condition that causes scarring (fibrosis) of a patients’ lungs which makes breathing increasingly difficult as the lungs become stiffer and lose their elasticity. The lungs become less efficient at transferring oxygen so that when someone with IPF breathes in, the transfer of oxygen through air sacs in their lungs and into their blood stream is impaired. Lung damage from IPF is irreversible, and there is currently no treatment that stops or reverses the scarring. In the US there are around 495 cases per 100,000 people, with median survival estimated at 2–5 years from the time of diagnosis. (2) (3)

References

(1) Cell Communication and Signaling paper, “LPA1-mediated inhibition of CXCR4 attenuates CXCL12-induced signaling and cell migration”: https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01261-7

(2) American Lung Association data on IPF:

https://www.lung.org/lung-health-diseases/lung-disease-lookup/idiopathic-pulmonary-fibrosis

(3) PubMed paper on incidence and prevalence of IPF: https://pubmed.ncbi.nlm.nih.gov/27126689/

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a clinical-stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data.

The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. 

The company has an ongoing US Phase 2 clinical trial assessing the efficacy of the combination of GPC-100 and propranolol in patients with multiple myeloma. In addition, the company is engaged in active collaborations with domestic and international biotechnology companies.

By targeting the unique pharmacology of GPCR pairs, the company aims to develop life-changing treatments for cancer and other diseases. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation.

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn.

For more information, please contact:

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

About Bridge Biotherapeutics, Inc.

Bridge Biotherapeutics Inc., based in the Republic of Korea and the U.S., is a publicly traded, clinical-stage biotech company founded in 2015. Bridge Biotherapeutics is engaged in the discovery and development of novel therapeutics, focusing on therapeutic areas with high unmet needs, including fibrotic diseases and cancers. The company is developing BBT-877, a novel autotaxin inhibitor for the treatment of fibrotic diseases including idiopathic pulmonary fibrosis (IPF), and BBT-207, a potent targeted cancer therapy for non-small cell lung cancer (NSCLC) with EGFR C797S mutations. Learn more at https://www.bridgebiorx.com/en/.

Paper in PLOS ONE Reinforces Potential for Combination Therapy in Hematological Malignancies

Seoul, Korea, & Redwood City, California, 26 October 2023 – GPCR Therapeutics, Inc., a clinical stage international biopharmaceutical company with an innovative approach to developing cancer therapeutics based on targeting G Protein Coupled Receptors (GPCR) pairs, announces publication of a research paper in PLOS ONE. The paper shows that the company’s lead small molecule asset, GPC-100, a novel CXCR4 antagonist and a potent hematopoietic stem cell (HSC) mobilizer, when combined with the beta-adrenergic receptor blocker propranolol, results in a significant increase in circulating HSCs in mice. These findings strongly support the use of this combination for peripheral blood HSC harvest in autologous stem cell transplant treatment in hematological cancers. 

The paper, authored in collaboration with Seoul National University’s School of Biological Sciences and Institute of Microbiology, is entitled, “GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol” (1).

The authors highlight that GPC-100 alone shows greater mobilization efficacy than a drug already approved for stem cell mobilization. Importantly, when combined with propranolol, GPC-100-induced HSC mobilization increases by another 2-fold. The mobilization efficiency by GPC-100 plus propranolol is similar to that of the standard of care treatment with granulocyte-colony stimulating factor (G-CSF). Together, this study suggests a strategy with a potential to mobilize sufficient HSC without the use of G-CSF, and thereby reduce the risk of G-CSF associated moderate to severe side effects such as severe bone pain. This also provides a better stem cell transplant treatment option for cancer patients with autoimmune diseases which may be exacerbated by G-CSF or sickle cell disease, where it is contraindicated. Finally, the paper supports that the triple combination of GPC-100 plus propranolol and G-CSF mobilizes a greater number of HSCs compared to the standards of care and is predicted to be a best-in-class mobilizer.

 Dr. Dong Seung Seen, GPCR Therapeutics’ founder and CEO, commented, “This latest high-quality paper, produced in close collaboration between our Korean and US sites, together with, Seoul National University, shines a spotlight on the potential for our lead asset, GPC-100, to be used with propranolol as a combination therapy for hematological malignancies, including multiple myeloma. Our discovery of this powerful functional relationship provides new hope in this notoriously hard to treat cancer.”

Hematological malignancies, such as multiple myeloma, are hard to treat. Increasingly, clinicians are using Autologous Stem Cell Transplant (ASCT) to treat patients, which has improved the anti-cancer response and survival compared to conventional chemotherapy. However, for ASCT to work well, hematopoietic stem cells, especially CD34+ cells, need to be successfully mobilized out of the patient’s bone marrow and into their peripheral blood, where the cells are more easily collected, and can then be stored for later transplantation. A key limiting factor is that mobilization is often inadequate, and insufficient cells are harvested for use in the patient’s treatment. This paper reports on how this common treatment limitation could be overcome through use of a combination of GPC-100 and propranolol.

As announced on 17 January 2023, the company has initiated a phase 2 trial in the US for GPC-100, which targets CXCR4, one of the most prevalent chemokine GPCRs over-expressed in more than 23 cancers. This randomized, open-label phase 2 study assesses the efficacy of GPC-100 and propranolol, with and without G-CSF, for the mobilization of stem cells in patients with multiple myeloma undergoing ASCT. The paper announced today supports this clinical trial.

References

(1) https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0287863

※ More than 35% of FDA approved drugs are GPCRs. Still, GPCRs’ complex pharmacology arising from their interactions with other GPCRs presents unique opportunities for drug development.

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data.

The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers.

The company has recently initiated a US Phase 2 clinical trial assessing the efficacy of the combination of GPC-100 and propranolol in patients with multiple myeloma. In addition, the company is engaged in active collaborations with domestic and international biotechnology companies.

By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation.

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn.

For more information, please contact:

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

• GPCR Therapeutics Expands Pipeline into Fibrosis with a Combination Approach Targeting LPA1

   

  Seoul, Korea, & Redwood City, California, 10 October 2023 – GPCR Therapeutics, Inc., a clinical-stage, international biopharmaceutical company, announced today the expansion of its pipeline into fibrosis with the publication of a paper in Cell Communication and Signaling. The paper, authored in collaboration with Seoul National University’s School of Biological Sciences and Institute of Microbiology, supports the need to fully inhibit two signaling receptors, lysophosphatidic acid receptor 1 (LPA₁) and CXCR4, for the effective treatment of Idiopathic Pulmonary Fibrosis (IPF).

  IPF is a progressive chronic lung condition that causes scarring (fibrosis) of a patients’ lungs which makes breathing increasingly difficult as the lungs become stiffer and lose their elasticity. The lungs become less efficient at transferring oxygen so that when someone with IPF breathes in, the transfer of oxygen through air sacs in their lungs and into their blood stream is impaired. Lung damage from IPF is irreversible, and there is currently no treatment that stops or reverses the scarring. In the US there are around 495 cases per 100,000 people, with median survival estimated at 2–5 years from the time of diagnosis. (1) (2)

  LPA₁ and CXCR4 are among the few targets for which IPF therapeutics are being clinically developed respectively. However, this research shows that an IPF therapeutic approach based on inhibiting only LPA₁ is likely to be insufficient, as CXCR4, which has been repressed by LPA₁, will be activated and induce aberrant cell signaling. The paper “LPA₁-mediated inhibition of CXCR4 attenuates CXCL12-induced signaling and cell migration” reports that complete inhibition of cell migration was only achieved in the presence of both CXCR4 and LPA₁ antagonists. (3)

  GPCR Therapeutics, Inc. is developing a diverse pipeline targeting both CXCR4, one of the most prevalent chemokine GPCRs overexpressed in more than 23 cancers, and other GPCRs that promote or inhibit CXCR4. The company’s lead pipeline targets CXCR4 and B2AR (beta-2 adrenergic receptor) in cancer and is currently undergoing a phase 2 clinical trial. Based in part on the research announced today, the company has expanded its portfolio and begun developing a pipeline targeting CXCR4 and LPA₁ in fibrosis.

  Dr. Pina Cardarelli, GPCR’s CSO and President of US operations, commented, “This paper showcases the high quality of the research into understanding the pathological role of GPCRs in cancer and inflammatory diseases. It is another example of the potential of our CXCR4-GPCR pairs approach, where several novel valuable mechanisms can be discovered. We are very eager to leverage our combination approach and explore the field of fibrosis.”

  GPCR recently launched a US phase 2 trial of GPC-100 in combination with Propranolol for stem cell mobilization in patients with multiple myeloma.

  References

  (1) https://www.lung.org/lung-health-diseases/lung-disease-lookup/idiopathic-pulmonary-fibrosis

  (2) https://pubmed.ncbi.nlm.nih.gov/27126689/

  (3)https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01261-7

   

  About GPCR Therapeutics

  GPCR Therapeutics, Inc. is a clinical-stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary G Protein Coupled Receptors (GPCR) data. The company’s proprietary data-driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identifying the best GPCR pair to target for specific disease indications and patient subpopulations creates a precision approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life-changing treatments for cancer and other diseases.

  GPCR Therapeutics is developing multiple programs with the aim of advancing therapies for hematological malignancies as well as solid tumors. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. Furthermore, the company has identified LPA₁ as a CXCR4 interactor that represses CXCR4 activity.

  The company has recently initiated a US Phase 2 clinical trial assessing the efficacy of the combination of GPC-100 and Propranolol in autologous stem cell transplant in patients with multiple myeloma. In addition, the company is engaged in active collaborations with domestic and international biotechnology companies, including Australia’s AdAlta.

  GPCR Therapeutics is headquartered in Seoul, Korea, with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn.

   

  For more information, please contact:

  GPCR Therapeutics (in Seoul)

  DaYoon Kim – Business Development Manager

  Tel: +82-2-878-2848

  dayoon.kim@gpcr.co.kr

• GPCR Therapeutics Demonstrates Clinical Improvement in Mobilization of Hematopoietic Stem Cells Using GPC-100/Burixafor in Clinical Pharmacology in Drug Development

Seoul, Korea, & Redwood City, California, 15 August 2023 – GPCR Therapeutics, Inc., a clinical stage, international biopharmaceutical company with an innovative approach to drug discovery based on targeting G Protein Coupled Receptors (GPCR) pairs, announced today publication of their paper in Clinical Pharmacology in Drug Development (1), in collaboration with Taiwan’s TaiGen Biotechnology Co. Ltd. The paper is entitled, “Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC-100), a Novel C-X-C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem/Progenitor Cells, in Mice and Healthy Subjects.” The results demonstrate that the company’s lead small molecule asset, GPC-100/burixafor, is generally safe and well tolerated. PK profile and marked increase of peripheral CD34+ cells after GPC-100 administration support further clinical development of GPC-100 for mobilization of hematopoietic stem/progenitor cells.

Adequate mobilization of hematopoietic stem cells (HSC), especially CD34+ cells, is necessary for stem cell transplantation in patients with hematological malignancies. GPC-100 is an inhibitor of the C-X-C chemokine receptor 4 (CXCR4) that disrupts the CXCL12/CXCR4 axis in the bone marrow releasing HSCs into circulation. Going further from mice studies, GPC-100 was administered intravenously to 64 healthy subjects in a randomized, double-blind, placebo-controlled single ascending dose study (0.10 to 4.40 mg/kg in eight cohorts) to evaluate safety, pharmacokinetics, and pharmacodynamics. As expected, white blood cells, CD133+ and CD 34+ cell concentrations generally increased with the increases in GPC-100 dose from 0.10 to 3.14 mg/kg. At maximal levels, the CD34+ cell counts increased 3- to 14-fold from baseline levels.

Dr. Dong Seung Seen, GPCR Therapeutics’ founder and CEO, commented, “Following on from our paper in March in Nature Scientific Reports, this paper is crucial as it represents yet another case for our drug development program to be peer-reviewed and validated in academia. This paper provides strong scientific evidence that GPC-100 is an excellent molecule to be used in our combination treatment program for better patient outcomes that any CXCR4 inhibitor cannot achieve alone.”

GPCR Therapeutics, Inc. is developing a diverse pipeline targeting CXCR4, one of the most prevalent chemokine GPCRs overexpressed in more than 23 cancers. The company has demonstrated more potent effect of CXCR4 inhibitors when administered in combination with other GPCR inhibitors than when given alone. A Phase 2 clinical trial of the combination of the CXCR4 inhibitor GPC-100 and the ADRB2 inhibitor propranolol is currently underway in the United States.

References

(1) https://accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.1302

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s proprietary data driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identification of the best GPCR pair to target for specific disease indications and patient subpopulations creates a personalized approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases.

GPCR Therapeutics is developing multiple programs with the aim of advancing therapies for hematological malignancies as well as solid tumors. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. The company has recently initiated a US Phase 2 clinical trial assessing the efficacy of the combination of GPC-100 and Propranolol in patients with multiple myeloma. In addition, the company is engaged in active collaborations with domestic and international biotechnology companies including Australia’s AdAlta (ASX: 1AD).

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn.

For more information, please contact:

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

• GPCR Therapeutics plans to apply for the Listing Eligibility Review in H2 and aims to list on KOSDAQ by the end of the year

Seoul, Korea, 27 June 2023 – GPCR Therapeutics, Inc., a clinical stage, international biopharmaceutical company with an innovative approach to drug discovery based on targeting G Protein Coupled Receptors (GPCR) pairs, announced today that the company passed the Technology Evaluation process for listing on the KOSDAQ market.

The Korea Exchange (KRX) offers a Special Listing Track that grants flexibility to companies with strong technology capabilities for listing on the market. The first phase of this procedure is called Technology Evaluation, where companies’ financial performance, business operations, commercial prospects are rigorously reviewed and graded by two external evaluation bodies. Only those who receive ratings over at least A-BBB are eligible to proceed to the next phase, the Listing Eligibility Review. GPCR Therapeutics received A-BBB grades, validating its strong performance, growth potential, and robust business model.

GPCR Therapeutics develops a diverse pipeline targeting CXCR4, one of the most prevalent chemokine GPCRs overexpressed in more than 23 cancers. CXCR4 plays an important role in cancer growth, metastasis, and drug resistance. The company has discovered that CXCR4 inhibitors demonstrate more potent effect when administered in combination with other GPCR inhibitors than when given alone. Based on this finding, a Phase 2 clinical trial of the combination of the CXCR4 inhibitor GPC-100 and the ADRB2 inhibitor propranolol is currently underway in the United States. In addition, the company has partnered up with various domestic and foreign biotech companies, including TaiGen Biotechnology in Taiwan and AdAlta in Australia and actively conducting collaborative research projects.

Dr. Dong Seung Seen, GPCR Therapeutics’ founder and CEO, commented, “The technical evaluation process is a critical step in the IPO journey as it paves the way for its entry into the public markets. I am glad we received favorable results, validating growth potential in our science as well as business. I would also like to express gratitude to our entire team for having achieved such significant milestone. Understanding the interactions between GPCRs is the key to overcoming the current hurdles of drug discovery. We are determined to expand our portfolio, and are gearing up for our next clinical trial for patients with other hematologic malignancies.”

Upon completion of the pre-IPO funding round, GPCR Therapeutics plans to apply for the Eligibility Review, and aims to list on the KOSDAQ within this year.

For more information, please contact:

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s proprietary data driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identification of the best GPCR pair to target for specific disease indications and patient subpopulations creates a personalized approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases.

GPCR Therapeutics is developing multiple programs with the aim of advancing therapies for hematological malignancies as well as solid tumors. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. The company has recently initiated a US Phase 2 clinical trial assessing the efficacy of the combination of GPC-100 and Propranolol in patients with multiple myeloma. In addition, the company is engaged in active collaborations with domestic and international biotechnology companies including Australia’s AdAlta (ASX: 1AD). GPCR Therapeutics aims to list on KOSDAQ in 2023.

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn

• • CXCR4-HRH1 heteromer identified as a potential therapeutic target for anticancer therapy

  Seoul, Korea, & Redwood City, California, 15 March 2023 – GPCR Therapeutics, Inc., a clinical stage, international biopharmaceutical company focused on targeting G Protein Coupled Receptors (GPCR) pairs, announced publication of a paper in Nature Scientific Reports (1), in collaboration with the School of Biological Sciences, Seoul National University (Seoul, Republic of Korea). The paper is entitled ‘Simultaneous activation of CXC chemokine receptor 4 and histamine receptor H1 enhances calcium signaling and cancer cell migration.’

  CXC chemokine receptor 4 (CXCR4) is a well-known GPCR overexpressed in more than 23 types of cancer and plays an important role in tumor metastasis. The team, led by Professor Won-Ki Huh, shows that another GPCR known as histamine receptor H1 (HRH1) is widely expressed in various cancer cell lines and cancer tissues, and that the level of co-expression of CXCR4 and HRH1 is related to poor prognosis in breast cancer patients. The simultaneous expression of both receptors leads to the formation of CXCR4-HRH1 heteromer, and this complex demonstrates enhanced signalling and migration capabilities.

  These findings suggest the interaction of CXCR4 and HRH1 may play an important role in cancer progression, thus serving as a potential therapeutic target for anticancer therapy.

  Dr. Michel Bouvier, a world-renowned expert in the field of GPCRs working as a professor and CEO at the Institute for Research in Immunology and Cancer (IRIC)  at Université de Montréal said, “This paper shows that the co-expression of the CXCR4 chemokine receptor and the H1 histamine receptor is associated to a poor prognostic and shorter overall and progression-free survival in breast cancer patients. This synergism between CXCR4 and HRH1 was observed not only in breast cancer cells but also in other cancer cells in which both receptors are expressed, suggesting a possible generalization of this cross-talk mechanism in oncogenesis. The observation that CXCR4 and HRH1 can form heterodimers in live cells suggest that such heterodimerization may underlie the observed synergism between the two receptors and open the possibility of targeting such heterodimer for the development of anti-cancer drugs.”

  “We are on a scientific journey to find more efficacious cancer treatments, delivering better patient outcomes,” commented Dr. Dong Seung Seen, GPCR’s founder and CEO. “We believe understanding the interactions between GPCRs is the key to overcoming the current hurdles of drug discovery. This publication is significant as it represents the first case for our co-targeting drug development strategy to be peer-reviewed and validated in academia. In addition to the ongoing combination treatment program using a CXCR4 inhibitor, GPC-100, and an ADRB2 inhibitor, Propranolol, we plan to expand our pipeline by targeting the interaction of CXCR4 and other GPCRs in the development of anticancer drugs.”

  GPCR recently announced the launch of a US phase 2 trial of GPC-100 in combination with Propranolol for stem cell mobilization in patients with multiple myeloma (2).

  References

  (1) Simultaneous activation of CXC chemokine receptor 4 and histamine receptor H1 enhances calcium signaling and cancer cell migration:

  https://www.nature.com/articles/s41598-023-28531-1

  (2) http://gpcr.co.kr/news/

  – Ends –

  Media contacts:

  GPCR Therapeutics (in Seoul)

  DaYoon Kim – Business Development Manager

  Tel: +82-2-878-2848

  dayoon.kim@gpcr.co.kr

   

  Scius Communications (in London)

  Katja Stout

  Tel: +44 778 943 5990

  katja@sciuscommunications.com

   

  Daniel Gooch

  Tel: +44 774 787 5479

  daniel@sciuscommunications.com

    

  About GPCR Therapeutics

  GPCR Therapeutics, Inc. is a venture-backed, clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s proprietary data driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identification of the best GPCR pair to target for specific disease indications and patient subpopulations creates a personalized approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases.

  GPCR Therapeutics has multiple programs in pre-clinical development with the aim of advancing therapies for multiple solid tumors as well as hematological malignancies. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, and has demonstrated safety and efficacy in US Phase 2 clinical trial. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. This combination therapy is currently undergoing Phase 2 clinical trial in the US. The company is collaborating with Australia’s AdAlta on novel cancer therapeutics.

  GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn

• The trial will evaluate the safety and efficacy of GPCR’s CXCR4-targeting stem cell mobilizer, GPC-100, in combination with propranolol
• The trial will also evaluate the potential of the combined treatment to replace G-CSF

Seoul, Korea, & Redwood City, California, 17 January 2023 – GPCR Therapeutics, Inc., a venture-backed, clinical stage, international biopharmaceutical company with an innovative approach to drug discovery based on targeting G Protein Coupled Receptors (GPCR) pairs, announced today the initiation of their phase 2 trial in the US for its lead small molecule asset, GPC-100.  GPC-100 targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in more than 23 cancers.

This randomized, open-label phase 2 study assesses the efficacy of GPC-100 and propranolol, with and without granulocyte colony-stimulating factor (G-CSF) for the mobilization of stem cells in patients with multiple myeloma undergoing autologous stem cell transplant. Propranolol blocks beta adrenergic receptors, also part of the GPCR family of proteins. G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. The trial is for up to 40 adult patients who will be enrolled at cancer centers in the USA. The trial will include a total of ten clinical sites, with University of Massachusetts Chan Medical School selected as the first clinical site to be activated. Muthalagu Ramanathan, M.D. will serve as the Principal Investigator. Trial completion is expected to be in the summer of 2024.

Dr. Dong Seung Seen, GPCR’s founder and CEO, said, “The initiation of this Phase 2 trial is the result of lengthy and meticulous work by our teams in California and Seoul. I thank them for their unwavering dedication and determination to make a difference to people with cancer.”

Dr. Omar Nadeem, Clinical Director for Myeloma Cellular Therapies Program at the Dana-Farber Cancer Institute, and a member of GPCR’s Scientific Advisory Board, commented, “This trial is studying novel strategies for stem cell collection in multiple myeloma, including a non-G-CSF approach and evaluating the role of propranolol in enhancing stem cell collection yield. This would allow for improved patient experience by making the process more efficient while limiting the toxicity of the currently utilized methods.” 

Dr. Pina Cardarelli, GPCR’s CSO and President of U.S. operations, said, “This is a major milestone on our scientific journey to discover specific combinations of drugs that are more efficacious for cancer treatment, delivering better patient outcomes.”

Multiple myeloma is a cancer that forms in a type of white blood cell called a plasma cell, which, when healthy, help fight infections by making antibodies that recognize and attack germs. In multiple myeloma, cancerous plasma cells accumulate in the bone marrow and crowd out healthy blood cells, no longer producing helpful antibodies, but abnormal proteins that can cause complications, such as bone pain and kidney abnormalities. In 2019, over 32,000 patients in the US were diagnosed with this disease, with a median age of 68 years at diagnosis. (1)

Reference

(1) https://rarediseases.org/rare-diseases/multiple-myeloma/

– Ends –

Media contacts: 

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

Scius Communications (in London)

Katja Stout

Tel: +447789435990

katja@sciuscommunications.com

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a venture-backed, clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s proprietary data driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identification of the best GPCR pair to target for specific disease indications and patient subpopulations creates a personalized approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases.

GPCR Therapeutics has multiple programs in pre-clinical development with the aim of advancing therapies for multiple solid tumors as well as hematological malignancies. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. The company is collaborating with Australia’s AdAlta (ASX: 1AD) on novel cancer therapeutics.

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn.

• AdAlta and GPCR Therapeutics form collaboration to evaluate a new cancer treatment approach combining beta blockers plus AdAlta’s CXCR4-inhibiting i-bodies.
• CXCR4 is overexpressed in more than 23 cancers and drugs targeting the CXCR4 pathway address a multi-billion dollar opportunity.
• AdAlta has the first option to license and further commercialise any products resulting from the collaboration.

MELBOURNE Australia and SEOUL South Korea, 13 October 2022: AdAlta Limited (ASX:1AD), the clinical stage drug discovery company developing novel therapeutic products from its i-body platform and GPCR Therapeutics Inc, a clinical stage biotech company discovering and developing innovative therapeutics targeting cancer based on the novel science of CXCR4, announce a collaboration to evaluate AdAlta’s CXCR4 inhibiting i‑bodies as cancer therapeutics, using GPCR Therapeutics’ proprietary combination inhibition approach.

AdAlta’s i-body platform is ideally suited to engaging an important class of drug targets called G-protein coupled receptors (GPCRs). One of these GPCRs is known as CXCR4. In addition to its role in fibrotic disease, CXCR4 is also known to be over-expressed in more than 23 cancers, representing a multi-billion dollar drug market. Attempts by others to develop CXCR4 inhibitors as cancer therapeutics have had limited success to date.

AdAlta owns a panel of i-bodies which inhibit CXCR4 signalling in different ways. The panel includes AD-214, AdAlta’s lead drug candidate which has been progressed to clinical development for fibrotic diseases.

GPCR Therapeutics has discovered that combining CXCR4 inhibitors with molecules inhibiting other GPCRs that are associated with CXCR4 in cancer can result in superior inhibition of CXCR4.

AdAlta’s CEO and Managing Director, Tim Oldham, commented:

“We are delighted to announce this collaboration with GPCR Therapeutics. Through the program, we hope to demonstrate that AdAlta’s i-bodies, when combined with other GPCR inhibitors can have enhanced therapeutic outcomes in cancer, in comparison with the typical approach of inhibiting individual GPCRs. This collaboration is consistent with our strategy of expanding the commercial use of our i-bodies in a cost-effective way.”

GPCR Therapeutics’ CEO, Dong Seung Seen, commented:

“We are pleased to be working with AdAlta’s expert team to explore synergies between our approach for combination inhibition of GPCRs and AdAlta’s i-body technology. We believe combining AdAlta’s unique i-body technology with our innovative CXCR4 combination therapy-based approach could lead to best-in-class anticancer drugs.”

Under the collaboration, AdAlta will supply a panel of its CXCR4 inhibiting i-bodies. GPCR Therapeutics will evaluate those i-bodies in combination with a series of generic beta blocker molecules selected from its own platforms which inhibit a GPCR known as B2AR. These studies will evaluate the effect of the combined CXCR4-B2AR inhibition on in vitro cell signalling, cell migration and cell killing. If successful, GPCR Therapeutics will evaluate the combined inhibition of these compounds in vivo in mouse cancer models.

If those studies are successful, AdAlta will have the first option to license and further commercialise resulting products for treating cancer, while GPCR Therapeutics will have the same option if it is not exercised by AdAlta. The parties have agreed that whichever is the licensee under these options will pay the other pre-agreed up-front option exercise fees, development milestones, commercialisation milestones and low- to mid- single digit royalties on sales, subject to development success.

The supply of the initial panel of i-bodies under the collaboration agreement will not have a material impact on AdAlta’s cash runway or other programs.

GPCR Therapeutics were advised by Liberi Group’s CEO, Frans Trouwen.

Authorised for lodgement by:

Tim Oldham

CEO and Managing Director
September 2022

Notes to Editors

About AdAlta

AdAlta Limited is a clinical stage drug development company headquartered in Melbourne, Australia. The Company is using its proprietary i-body technology platform to solve challenging drug targeting problems and generate a promising new class of single domain antibody protein therapeutics with the potential to treat some of today’s most challenging medical conditions.

The i-body technology mimics the shape and stability of a unique and versatile antigen binding domain that was discovered initially in sharks and then developed as a human protein. The result is a range of unique proteins capable of interacting with high selectivity, specificity and affinity with previously difficult to access targets such as G-protein coupled receptors (GPCRs) that are implicated in many serious diseases. i-bodies are the first fully human single domain antibody scaffold and the first based on the shark motif to reach clinical trials. 

AdAlta has completed Phase I clinical studies for its lead i-body candidate, AD-214, that is being developed for the treatment of Idiopathic Pulmonary Fibrosis (IPF) and other human fibrotic diseases for which current therapies are sub-optimal and there is a high unmet medical need. AdAlta has a second target in discovery research, also in the field of fibrosis and inflammation.

The Company is also entering collaborative partnerships to advance the development of its i‑body platform. It has a collaboration with Carina Biotech to co-develop precision engineered, i-body enabled CAR-T cell therapies (i-CAR-T) to bring new hope to patients with cancer. It has an agreement with GE Healthcare to co-develop i-bodies as diagnostic imaging agents (i‑PET imaging) against Granzyme B, a biomarker of response to immuno-oncology drugs, a program now in pre-clinical development.

AdAlta’s strategy is to maximise the products developed using its next generation i-body platform by internally discovering and developing selected i-body enabled product candidates against GPCRs implicated in fibrosis, inflammation and cancer and partnering with other biopharmaceutical companies to develop product candidates against other classes of receptor, in other indications, and in other product formats.

Further information can be found at: https://adalta.com.au 

For more information, please contact:

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a venture-backed, clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s proprietary data driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identification of the best GPCR pair to target for specific disease indications and patient subpopulations creates a personalized approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases.

GPCR Therapeutics has multiple programs in pre-clinical development with the aim of advancing therapies for hematological malignancies as well as multiple solid tumors. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation. 

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in Redwood City, California, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn.

For more information, please contact:

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

Scius Communications (in London)

Katja Stout

Tel: +447789435990

katja@sciuscommunications.com

Redwood City, California, September 08, 2022 – GPCR Therapeutics, Inc., a venture-backed clinical stage international biopharmaceutical company with an innovative approach to drug discovery based on targeting G Protein Coupled Receptors (GPCR) pairs, today announced that to accommodate the expansion of its US subsidiary, it has relocated from incubator space in San Carlos. GPCR’s US operations will be based in new office and laboratory space at 400 Seaport Court, Redwood City, a premier location for biotech research in the San Francisco Bay Area.

GPCR’s founder and CEO, Dr. Dong Seung Seen, said, “We are delighted to be growing in one of the world’s biggest and best biotech clusters, as neighbors to pharma companies including AbbVie and Bristol Myers Squibb, and many other innovation-driven biotech companies.”

GPCR’s CSO and President of US operations, Dr. Pina Cardarelli, said, “We believe our science will lead to the discovery of specific combination drugs that are more efficacious for cancer treatment, thereby leading to better patient outcomes.”

The new US location has over 8,000 square feet covering one floor, dedicated to GPCR’s R&D efforts and will accommodate capabilities in cell culture, protein engineering, computational chemistry, and high-throughput screening. In addition, GPCR’s new site has ample room for growth, as the current team of 10 employees is expected to nearly double over the coming year.

As GPCR expands, it is actively recruiting to its scientific teams to scale up its R&D programs and start clinical trials.

“We will be proud to launch our first human clinical trials, resulting from outstanding work done over many years by our exceptional teams in South Korea and the USA” concluded Dr. Seen.

GPCR Therapeutics has recently become a member of the San Mateo County Chamber of Commerce.

The company will officially open the new US subsidiary on September 15^th with a ribbon cutting ceremony at 11:00 a.m.

– Ends –

Media contacts:

GPCR Therapeutics (in Redwood City)

Seulki Kim

Tel: +1-206-234-3125

slkikim@gpcr.co.kr

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

Scius Communications (in London)

Katja Stout

Tel: +447789435990

katja@sciuscommunications.com

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a venture-backed, clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s proprietary data driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identification of the best GPCR pair to target for specific disease indications and patient subpopulations creates a personalized approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases.

GPCR Therapeutics has multiple programs in pre-clinical development with the aim of advancing therapies for multiple solid tumors as well as hematological malignancies. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation.

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, visit gpcr.co.kr and follow us on LinkedIn.

Seoul, South Korea, 28 April 2022 – GPCR therapeutics, Inc., a venture-backed clinical stage international biopharmaceutical company with an innovative approach to drug discovery based on targeting G Protein Coupled Receptors (GPCR) pairs, today announced four appointments to its Scientific Advisory Board (SAB). Dr. Michel Bouvier, Dr. Luisa Salter-Cid, Dr. Omar Nadeem and Dr. Jon Wigginton will provide scientific expertise to support the company’s research and clinical development. GPCR just had a very successful first meeting including all the Scientific Advisory Board.

GPCR’s CEO, DongSeung Seen, said, “We are delighted to welcome our four distinguished new SAB members. They bring a wealth of scientific knowledge which will be of great help in progressing our lead small molecule asset, GPC-100/Burixafor, and advancing our therapies for multiple solid tumours and haematological malignancies. I look forward to working with them all as we discover and develop innovative therapeutics targeting cancer based on the novel science of GPCR heteromers.”

Dr. Michel Bouvier is a professor of Biochemistry and Molecular Medicine and principal investigator at the Institute for Research in Immunology and Cancer (IRIC) of the Université de Montréal, and has been CEO of IRIC since 2014, and was CEO of IRICoR, a non-profit centre of excellence for commercialization and research for 5 years. He is a world-renowned expert in the field of GPCRs. He obtained his B.Sc. in biochemistry and his Ph.D in Neurological Sciences from the Université de Montréal. He was a post-doctoral fellow at Duke University in the laboratory of the Nobel Laureate, Robert J. Lefkowitz.

Dr. Luisa Salter-Cid is a strategic R&D leader with extensive experience managing drug discovery teams. She has significant experience in drug discovery and development. Currently, she is the CSO of Pioneering Medicines at Flagship Pioneering, a life sciences venture capital company that invests in biotechnology, life sciences, and sustainability companies with successful portfolio companies including Moderna. She previously served as CSO for Gossamer Bio, a clinical-stage biopharmaceutical company focused on discovering, acquiring, developing and commercialising therapeutics in various disease areas. She was also the Vice President for Bristol-Myers Squibb leading the Immuno-oncology and Genomics teams. She obtained her B.Sc. in Biology from the University of Lisbon and her Ph.D in Immunology from the University of Miami.

Dr. Omar Nadeem is a Physician in Medical Oncology and specialises in clinical care and investigation in the field of Multiple Myeloma and plasma cell disorders. He is the Clinical Director for Myeloma Cellular Therapies Program at the Dana-Farber Cancer Institute. He obtained his B.Sc. in Biology from the University of Massachusetts and his MD in Medicine from Ross University, Dominica, West Indies.

Dr. Jon Wigginton is a physician-scientist with over 25 years expertise in cancer immunotherapy and oncology drug development, with leadership experience in both academia and industry. He currently serves as Senior Advisor and Chairman of the SAB at Cullinan Oncology, Inc., as well as on the Board of Directors of Sutro Biopharma and Checkmate Pharmaceuticals. Dr. Wigginton previously served as Chief Medical Officer of Cullinan Oncology, Inc., and as Chief Medical Officer at MacroGenics Inc., where he led the company’s clinical development programs. He has also held leadership positions at Bristol Myers Squibb and at Merck & Co. Early in his career, Dr. Wigginton worked at the National Cancer Institute for over 14 years and served as Head of the Investigational Biologics Section in the Center for Cancer Research. He earned his M.D. from the University of Michigan.

– Ends –

Media contacts:

GPCR Therapeutics (in Seoul)

DaYoon Kim – Business Development Manager

Tel: +82-2-878-2848

dayoon.kim@gpcr.co.kr

Scius Communications (in UK)

Katja Stout

Tel: +447789435990

katja@sciuscommunications.com

About GPCR Therapeutics

GPCR Therapeutics, Inc. is a venture-backed, clinical stage international biopharmaceutical company with an innovative approach to developing therapeutics built on its proprietary GPCR data. The company’s proprietary data driven approach has identified over 1,000 GPCR pairs upon which drug screening campaigns can be pursued. Identification of the best GPCR pair to target for specific disease indications and patient subpopulations creates a personalized approach to combination therapy. By targeting the unique pharmacology of GPCR pairs, the company aims to develop life changing treatments for cancer and other diseases.

GPCR Therapeutics has multiple programs in pre-clinical development with the aim of advancing therapies for multiple solid tumors as well as hematological malignancies. The company’s lead small molecule asset, GPC-100/Burixafor, targets CXCR4, one of the most prevalent chemokine GPCRs overexpressed in various cancers. The company has identified that CXCR4 interacts with the beta-2 adrenergic receptor (B2AR), and this GPCR pair presents an alternate signaling pathway that is synergistically dependent on CXCR4 and B2AR activation.  

GPCR Therapeutics has its HQ in Seoul, Korea with additional R&D facilities in the San Francisco Bay Area, USA. For more information, please visit gpcr.co.kr or follow us on LinkedIn.