Sonnet BioTherapeutics, Inc.

The maximum tolerated dose (MTD) of SON-1010 was set at 1200 ng/kg, without dose-limiting toxicity or evidence of cytokine release syndrome at any dose level Stable disease (SD) at four months post-initiation of dosing was seen in 10 of 21 (48%) evaluable monotherapy patients, and importantly included one patient dosed at the MTD who had a partial response (PR) by RESIST criteria (a 45% decrease from baseline) Together, these data suggest clinical benefit when SON-1010 is administered as a monotherapy Sonnet management discusses what this data means in a Virtual Investor “What This Means” segment; access here PRINCETON, NJ, Dec. 09, 2024 (GLOBE NEWSWIRE) -- Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) (the "Company" or "Sonnet"), a clinical-stage company developing targeted immunotherapeutic drugs, announced today that the results of SON-1010 at the highest dose have been formally evaluated by the Safety Review Committee in the Phase 1 SB101 clinical trial of SON-1010 (IL12-FHAB) in adult patients with advanced solid tumors. SB101 is the Company’s open-label, adaptive-design dose-escalation study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SON-1010 administered to patients with advanced solid tumors. The study has enrolled 24 subjects to date. Primary outcome measures for the study were to evaluate the safety and tolerability of SON-1010 and establish the MTD. Additionally, the Company announced the release of a “What This Means” segment to discuss the data which is now available here. SON-1010 is the Company’s proprietary version of recombinant human interleukin-12 (rhIL-12), configured using genetic fusion to Sonnet's Fully Human Albumin Binding (FHAB®) platform, which extends the half-life and bioactivity of the IL-12 component due to binding native albumin in the serum and also targets the tumor microenvironment (TME) by strong binding to gp60 and Secreted Protein Acidic and Rich in Cysteine (SPARC). “We are encouraged by this topline safety data generated to date in our Phase 1 study. Given the history of safety concerns with rhIL-12 in its first human trials over 25 years ago, it is exciting to see higher doses of SON-1010 demonstrating minimal toxicity, which is likely due to its unique biodistribution and albumin binding profile, with delivery to and retention in the tumor microenvironment,” said Richard Kenney, M.D., Sonnet's Chief Medical Officer. “We may finally be able to realize the promising antitumor effect that has been associated with this cytokine in preclinical models for decades. The IFNγ response, which is considered to be important for anti-tumor control, has been robust but controlled with a much longer return to baseline. While the clinical benefit we have been seeing during dose escalation has been reassuring, the PR at the highest dose is particularly important, as this suggests that there may be a synergistic effect in combination with checkpoint inhibitors and/or chemotherapy.” All enrolled patients have had advanced solid tumors. The final 1200 ng/kg dose-escalation cohort was increased in size to 6 patients to enhance the assessment of PK and PD at the MTD. The SB101 trial employed a ‘desensitizing’ first dose of 300 ng/kg to take advantage of the known tachyphylaxis with rhIL-12, with the intention of minimizing toxicity and allowing for higher maintenance doses. No dose-limiting toxicities or related serious adverse events (SAE) have occurred to date. The safety and toxicity profile that has developed is typical for a Phase 1 oncology trial, with the majority of adverse events (AEs) being reported as mild. All AEs seen to date have been transient, with no evidence of cytokine release syndrome. Of the 24 patients dosed to date, 17 (71%) had SD at the first follow-up CT, 12 of whom were progressing at study entry. 10 of the 21 evaluable patients (48%) remained stable at four months, suggesting SON-1010 clinical benefit, and one of those patients in the highest dose cohort, who has clear cell sarcoma, had a PR with a 45% reduction in tumor size by RESIST criteria. As previously disclosed, one patient in the first dose cohort with endometrial sarcoma who was progressing at study entry had evidence of improvement after 11 months, with smaller tumors and complete resolution of ascites. This patient later progressed at 23 months and started chemotherapy. “This topline safety data release on our lead program is a significant milestone for Sonnet’s clinical development. We have now successfully completed dose escalation in our first trial with SON-1010 and are pleased to see a partial response in one patient at the highest dose, in addition to clinical benefit in almost half of the evaluable patients,” said Pankaj Mohan, Ph.D., Sonnet Founder and Chief Executive Officer. “Safety of this extended PK version of IL-12 has been within expected levels and the comparison with dosing in healthy volunteers provided strong evidence of tumor targeting in humans. We have used this trial to establish the MTD and will continue to follow the patients currently being treated to assess longer-term safety and tumor responses. Sonnet is currently seeking partnership opportunities to help support later stage development of SON-1010.” For more information about the Phase 1 SB101 trial in adult patients with advanced solid tumors visit www.clinicaltrials.com and reference identifier NCT05352750. SON-1010 is also being evaluated in a Phase 1b/2a dose-escalation and proof-of-concept study (SB221) in combination with SON-1010 and atezolizumab (in collaboration with Genentech, a member of the Roche Group), which is focused on platinum-resistant ovarian cancer (PROC) (NCT05756907). Enrollment remains ongoing and an update on safety at the MTD in that trial is expected in Q1 2025. About SON-1010 SON-1010 is a candidate immunotherapeutic recombinant drug that links unmodified single-chain human IL-12 with the albumin-binding domain of the single-chain antibody fragment A10m3. This was selected to bind albumin both at normal pH, as well as at the acidic pH typically found in the TME. The FHAB technology targets tumor and lymphatic tissue, providing a mechanism for dose sparing and an opportunity to improve the safety and efficacy profile of not only IL-12, but a variety of potent immunomodulators that can be linked using the platform. Interleukin-12 can orchestrate a robust immune response to many cancers and pathogens. Given the types of proteins induced in the TME, such as the Secreted Protein and Rich in Cysteine (SPARC) and glycoprotein 60 (GP60), several types of cancer such as non-small cell lung cancer, melanoma, head and neck cancer, sarcoma, and some gynecological cancers are particularly relevant for this approach. SON-1010 is designed to deliver IL-12 to local tumor tissue, turning ‘cold' tumors ‘hot' by stimulating IFNγ, which activates innate and adaptive immune cell responses and increases the production of Programed Death Ligand 1 (PD-L1) on tumor cells. About the Phase 1 SB101 Trial This first-in-human study is primarily designed to evaluate the safety of multiple ascending doses of SON-1010 in cancer patients and is being conducted at several sites across the United States. While the optimal dose is unknown at this stage, the potential to target tumors, the extended PK mechanism, and our preclinical data suggest the therapeutic dose may be lower compared to native human IL-12. The study, utilizing a standard 3+3 oncology design in at least five cohorts, should establish the MTD using subcutaneous injections of SON-1010 every 3 to 4 weeks. The primary endpoint explores the safety and tolerability of SON-1010, with key secondary endpoints intended to measure PK, PD, immunogenicity, and anti-tumor activity. This study will form the basis for potential combinations with other types of immunotherapies and the future development of bispecific candidates using the FHAB platform. About Sonnet BioTherapeutics Holdings, Inc. Sonnet is an oncology-focused biotechnology company with a proprietary platform for developing targeted biologic drugs with single or bifunctional action. Known as FHAB (Fully Human Albumin-Binding), the technology utilizes a fully human single chain antibody fragment (scFv) that binds to and "hitch-hikes" on human serum albumin (HSA) for transport to target tissues. Sonnet's FHAB was designed to specifically target tumor and lymphatic tissue, with an improved therapeutic window for optimizing the safety and efficacy of immune modulating biologic drugs. FHAB platform is the foundation of a modular, plug-and-play construct for potentiating a range of large molecule therapeutic classes, including cytokines, peptides, antibodies and vaccines. Sonnet’s lead program, SON-1010, or IL-12-FHAB, is in development for the treatment of solid tumors and ovarian cancer. SON-1010 is being evaluated in an ongoing Phase 1/2a study through a Master Clinical Trial and Supply Agreement, along with ancillary Quality and Safety Agreements, with Roche in combination with atezolizumab (Tecentriq®) for the treatment of Platinum-Resistant Ovarian Cancer (PROC). The Company is also evaluating its second program, SON-1210, an IL12-FHAB-IL15 for solid tumors, in collaboration with the Sarcoma Oncology Center to commence an investigator-initiated and funded Phase 1/2a study for the treatment of pancreatic cancer. The Company’s SON-080 program is a low dose of rhIL-6 in development for Chemotherapy-Induced Peripheral Neuropathy (CIPN) and Diabetic Peripheral Neuropathy (DPN). SON-080 demonstrated encouraging results in a Phase 1b/2a clinical trial, being well tolerated with no evidence of a pro-inflammatory cytokine response. In October 2024, Sonnet announced an India license agreement with Alkem Laboratories, Inc. who will assume responsibility for advancing development of the SON-080 program into a Phase 2 study in DPN. Forward-Looking Statements This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the outcome of the Company’s clinical trials, the Company's cash runway, the Company's product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statements that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which we operate and management's current beliefs and assumptions. These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential," "predict," "project," "should," "would" and similar expressions and the negatives of those terms. These statements relate to future events or our financial performance and involve known and unknown risks, uncertainties, and other factors which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company's filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Investor Relations Contact:JTC Team, LLCJenene Thomas908-824-0775SONN@jtcir.com

Pankaj Mohan, CEO of Sonnet discusses what this publication means in a Virtual Investor “What This Means” segment; access here PRINCETON, NJ, Dec. 04, 2024 (GLOBE NEWSWIRE) -- Sonnet BioTherapeutics Holdings, Inc. (the "Company" or "Sonnet”) (NASDAQ: SONN), a clinical-stage company developing innovative targeted immunotherapeutic drugs, today announced the publication of extensive discovery, development and preclinical data on SON-1010 demonstrating its mechanism of action in Frontiers in Immunology. SON-1010, Sonnet’s lead proprietary drug candidate, combines the Company’s fully human albumin-binding (FHAB®) construct with a native single-chain IL-12 sequence to simplify delivery of the cytokine systemically. The paper entitled, “SON-1010: An Albumin-binding IL-12 Fusion Protein with Improved Cytokine Half-life Targets Tumors and Enhances Therapeutic Efficacy,” details the identification of single-chain variable fragments (scFv) from a human phage display library that bound human, mouse, and cynomolgus macaque serum albumin, both at physiologic and acidic conditions. The composition of matter patent claims on the FHAB domain and SON-1010 fusion protein have been issued in a number of major markets, including but not limited to the U.S., China, Japan, Russia and New Zealand, and expire between 2038 and 2039. Additionally, the Company announced the release of a “What This Means” segment to discuss the publication which is now available here.The extensive discovery program included putting the scFv domains through a series of steps to identify strongly binding molecules that bind tightly over a 5.8 to 7.2 pH range and do not interfere with the normal physiology of albumin to bind the neonatal Fc receptor (FcRn). This resulted in having prolonged half-life in serum and binding to SPARC/GP60, which allows albumin to target the tumor microenvironment (TME). A final molecule was selected and a single mutation was introduced that minimizes the potential for immunogenicity. This FHAB domain was characterized, and manufacturing processes were developed to prepare Sonnet’s first drug candidate for the clinic. Once identified, the murine form of mIL12-FHAB was shown to be much more efficient at blocking tumor growth compared to murine IL-12, while stimulating significant and prolonged IFNγ production with minimal toxicity. Biodistribution studies in mice confirmed tumor delivery and toxicological studies in non-human primates allowed the initiation of the clinical trials.“We are pleased to share these findings, which is the first time we have fully described the extensive research that was required to discover and develop our signature FHAB platform,” said Pankaj Mohan, Ph.D., Founder and CEO of Sonnet. “This work lays the foundation for all of the products on our platform that are designed to safely extend the half-life of cytokines and deliver them to the tumor, where they can convert the immunological response from ‘cold’ to ‘hot’ and potentially realize the promise of immunotherapy.”“IL-12 and related compounds have been extensively studied in cancer and immunotherapy indications. However, recombinant interleukins have had limited clinical success owing to their short circulating half-life, inefficient TME targeting, and requirement for frequent dosing, often leading to substantial systemic toxicities,” added John Cini, Ph.D. Co-Founder and CSO of Sonnet. “We believe we have addressed these issues with our discovered platform, having utilized a molecule that can be applied in any solid tumor type that concentrates albumin, such as sarcoma, gynecologic, and gastrointestinal cancers. We intend to explore new compounds as well, as funds become available.” The Company is currently conducting a Phase 1 clinical trial of SON-1010 (IL12-FHAB) as a monotherapy in adult patients with advanced solid tumors (SB101; NCT05352750). The Company expects to report safety data from this study in Q4 2024. SON-1010 is being evaluated in an ongoing Phase 1/2a study through a Master Clinical Trial and Supply Agreement, along with ancillary Quality and Safety Agreements, with Roche in combination with atezolizumab (Tecentriq®) for the treatment of Platinum-Resistant Ovarian Cancer (PROC). About Sonnet BioTherapeutics Holdings, Inc. Sonnet is an oncology-focused biotechnology company with a proprietary platform for developing targeted biologic drugs with single or bifunctional action. Known as FHAB (Fully Human Albumin-Binding), the technology utilizes a fully human single chain antibody fragment (scFv) that binds to and "hitch-hikes" on human serum albumin (HSA) for transport to target tissues. Sonnet's FHAB was designed to specifically target tumor and lymphatic tissue, with an improved therapeutic window for optimizing the safety and efficacy of immune modulating biologic drugs. FHAB platform is the foundation of a modular, plug-and-play construct for potentiating a range of large molecule therapeutic classes, including cytokines, peptides, antibodies and vaccines. Sonnet’s lead program, SON-1010, or IL-12-FHAB, is in development for the treatment of solid tumors and ovarian cancer. SON-1010 is being evaluated in an ongoing Phase 1/2a study through a Master Clinical Trial and Supply Agreement, along with ancillary Quality and Safety Agreements, with Roche in combination with atezolizumab (Tecentriq®) for the treatment of Platinum-Resistant Ovarian Cancer (PROC). The Company is also evaluating its second program, SON-1210, an IL12-FHAB-IL15 for solid tumors, in collaboration with the Sarcoma Oncology Center to commence an investigator-initiated and funded Phase 1/2a study for the treatment of pancreatic cancer. The Company’s SON-080 program is a low dose of rhIL-6 in development for Chemotherapy-Induced Peripheral Neuropathy (CIPN) and Diabetic Peripheral Neuropathy (DPN). SON-080 demonstrated encouraging results in a Phase 1b/2a clinical trial, being well tolerated with no evidence of a pro-inflammatory cytokine response. Sonnet is currently seeking partnership opportunities to support a Phase 2 trial. In October 2024, Sonnet announced an India license agreement with Alkem Laboratories, Inc. who will assume responsibility for advancing development of the SON-080 program into a Phase 2 study in DPN. Forward-Looking Statements This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the outcome of the Company’s clinical trials, the Company's cash runway, the Company's product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statements that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which we operate and management's current beliefs and assumptions. These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential," "predict," "project," "should," "would" and similar expressions and the negatives of those terms. These statements relate to future events or our financial performance and involve known and unknown risks, uncertainties, and other factors which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company's filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Investor Relations Contact:JTC Team, LLCJenene Thomas908-824-0775SONN@jtcir.com

Both novel bifunctional (SON-1411) and monofunctional (SON-1400) fusion proteins exhibit wild-type binding to the IL-18 receptor (IL-18Rc), coupled with undetectable binding to the inhibitory IL-18 binding protein (IL-18BP) IL-18 has significant importance for cancer immune-oncology and combination with IL-12 on Sonnet’s FHAB platform which Sonnet believes could present an important oncology possibility The lock-and-load flexibility of the FHAB platform offers the bifunctional payload capability of adding another synergistic biologics target to IL-18 generating multiple novel cancer drugs Nov. 06, 2024 -- Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) (the "Company" or "Sonnet"), a clinical-stage company developing targeted immunotherapeutic drugs, announced today that the United States Patent and Trademark Office (USPTO) has issued U.S. Patent No. 12,134,635 entitled “Interleukin 18 (IL-18) Variants and Fusion Proteins Comprising Same,” covering two of its novel drug candidates, SON-1411 (IL-18BPR-FHAB-IL12) and SON-1400 (IL-18BPR-FHAB), each containing a modified version of recombinant human interleukin-18 (IL-18BPR = Binding Protein Resistant). The patent carries a term effective until June 2044. “The issuance of this intellectual property is an important milestone that we believe provides significant differentiation from competitors trying to tap the full biological potential of IL-18, either alone or in combination with IL-12. IL-18 is a key cytokine that, when combined synergistically with IL-12, has the potential to be an important therapeutic asset for oncology and cell-based therapy,” commented Pankaj Mohan, Ph.D., Sonnet Founder and Chief Executive Officer. SON-1411 is a proprietary bifunctional fusion protein consisting of IL-18BPR combined with single-chain wild-type IL-12, linked to Sonnet's Fully Human Albumin Binding (FHAB®) platform, which has replaced SON-1410 as a development target. SON-1400 is a monofunctional fusion protein comprising the same IL-18BPR domain linked to the FHAB. FHAB extends the half-life and biological activity of linked molecules by binding native albumin in the serum and targets the tumor microenvironment (TME) through high affinity binding to glycoprotein 60 (gp60) and the Secreted Protein Acidic and Rich in Cysteine (SPARC). IL-18 can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. IL-18 acts synergistically with other pro-inflammatory cytokines to promote interferon-γ (IFN-γ) production by NK cells and T cells. Systemic administration of IL-18 has been shown to have anti-tumor activity in several animal models. Moreover, tumor-infiltrating lymphocytes (TILs) express more IL-18 receptors than other T cells. However, IL-18 clinical trials have shown that, although it is well tolerated, IL-18 has poor efficacy in the treatment of cancers, most likely due in large part to the high co-expression of IL-18 binding protein (IL-18BP) in the TME. In particular, IL-18BP serves as a “decoy receptor” that binds to IL-18 with higher affinity, compared with the IL-18Rc complex, thereby causing a negative feedback loop with IL-18 and inhibiting IL-18-mediated TIL activation. Thus, there exists a potential for the discovery of IL-18 variant compositions that could harness the therapeutic potential of IL-18 for the treatment of cancers. Sonnet’s strategy for amino acid modifications to rIL-18 was based on a compilation of literature review, 3D X-ray crystallography structures, and computer modeling analysis. Subsequently, certain IL-18 variant sequences were synthesized, engineered into expression constructs and manufactured at small scale in either CHO cell culture or E. coli. Highly purified milligram quantities of SON-1411 or SON-1400 were analyzed in vitro for IL-18Rc or IL-18BP binding activities, respectively, using the HEK-Blue™ and Bright-Glo Luciferase™ IL-18Rc reporter assays. In vitro results for at least one variant of IL-18 showed equivalent binding to the IL-18 Rc, compared to the wild-type IL-18 reference molecule, concomitant with no or reduced binding to IL-18BP. The known MOA of IL-18 inhibition by IL-18BP is reviving the importance of clinical applications of IL-18. IL-18BP has been shown to be elevated in cancer patients, thus nullifying the clinical applications of IL-18. Sonnet is developing two novel bifunctional cytokine molecules, IL-18BPR-FHAB-IL12 and IL-18BPR-FHAB, both of which contain a unique IL-18 domain that does not bind the inhibitor IL-18BP but still maintains full IL-18 and IL-12 bioactivity. The clinical application of these mono or bifunctional fusion proteins could potentially expand immunotherapy applications for cancer patients. SON-1411 is a candidate immunotherapeutic recombinant drug that is closely related to and has replaced SON-1410. SON-1410 links an unmodified single-chain human IL-18 and an unmodified IL-12 with the albumin-binding domain of the single-chain antibody fragment A10m3. The key difference between SON-1410 and SON-1411 is that in the latter, there has been novel modification of the IL-18 domain via mutagenesis to retain wildtype binding to the IL-18 receptor (IL-18 Rc) while inhibiting or abolishing binding to the IL-18 binding protein (IL-18 BP). The A10m3 scFv was selected to bind both at normal pH, as well as at the acidic pH that is typically found in the TME. The FHAB technology targets tumor and lymphatic tissue, providing a mechanism for dose sparing and an opportunity to improve the safety and efficacy profile of IL-18 and IL-12, as well as a variety of potent immunomodulators that can be added using the platform. Interleukin-12 can orchestrate a robust immune response to many cancers and pathogens. Given the types of proteins induced in the TME, such as SPARC and gp60, several types of cancer such as non-small cell lung cancer, melanoma, head and neck cancer, sarcoma, and some gynecological cancers are particularly relevant for this approach. SON-1411 is designed to deliver IL-18BPR and IL-12 to local tumor tissue, turning ‘cold’ tumors ‘hot’ by stimulating IFNγ, which activates innate and adaptive immune cell responses and increases the production of Programed Death Ligand 1 (PD-L1) on tumor cells. Sonnet is an oncology-focused biotechnology company with a proprietary platform for developing targeted biologic drugs with single or bifunctional action. Known as FHAB (Fully Human Albumin Binding), the technology utilizes a fully human single chain antibody fragment (scFv) that binds to and "hitch-hikes" on human serum albumin (HSA) for transport to target tissues. Sonnet's FHAB was designed to specifically target tumor and lymphatic tissue, with an improved therapeutic window for optimizing the safety and efficacy of immune modulating biologic drugs. FHAB platform is the foundation of a modular, plug-and-play construct for potentiating a range of large molecule therapeutic classes, including cytokines, peptides, antibodies and vaccines. Sonnet’s lead program, SON-1010, or IL-12-FHAB, is in development for the treatment of solid tumors and ovarian cancer. SON-1010 is being evaluated in an ongoing Phase 1/2a study through a Master Clinical Trial and Supply Agreement, along with ancillary Quality and Safety Agreements, with Roche in combination with atezolizumab (Tecentriq®) for the treatment of Platinum-Resistant Ovarian Cancer (PROC). The Company is also evaluating its second program, SON-1210, an IL12-FHAB-IL15 for solid tumors, in collaboration with the Sarcoma Oncology Center to commence an investigator-initiated and funded Phase 1/2a study for the treatment of Pancreatic Cancer. The Company’s SON-080 program is a low dose of rhIL-6 in development for CIPN and DPN. SON-080 demonstrated encouraging results in a Phase 1b/2a clinical trial, being well tolerated with no evidence of a pro-inflammatory cytokine response. Sonnet is currently seeking partnership opportunities to support a Phase 2 trial. The content above comes from the network. if any infringement, please contact us to modify.