On September 28, 2021 Cue Biopharma, Inc. (Nasdaq: CUE), a clinical-stage biopharmaceutical company engineering a novel class of injectable biologics to selectively engage and modulate targeted T cells directly within the patient’s body, reported the publication of research titled "Peptide-HLA-based immunotherapeutics platforms for direct modulation of antigen-specific T cells" in the peer-reviewed Nature journal, Scientific Reports (Press release, Cue Biopharma, SEP 28, 2021, View Source [SID1234608270]). The article describes Cue Biopharma’s IL-2 based CUE-100 series technology platforms, Immuno-STAT (Selective Targeting and Alteration of T cells) and Neo-STAT, being leveraged for the development of first-in-class biologics that enable selective activation of cancer-killing immune T cells within the patient’s body.

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"We believe our platforms address a significant challenge in immunotherapy of ensuring selective targeting of activation signals to anti-tumor T cells in the patient while sparing the indiscriminate systemic activation of the immune system," said Anish Suri, Ph.D., president and chief scientific officer of Cue Biopharma. "Adoptive cell therapy such as chimeric antigen receptor T-cell (CAR-T) therapies have demonstrated highly encouraging results for some patients but remain limited by the need of cellular ex-vivo manipulation and manufacturing challenges. Similarly, systemic approaches with immunostimulatory molecules, such as interleukin 2 (IL-2) or bispecific molecules, activate T cells indiscriminately and are associated with common severe adverse events, significantly limiting clinical benefit and applicability. Cue Biopharma’s approach and resulting platform, represents a potential breakthrough in the ability to selectively and safely modulate the immune system in a highly controlled and targeted manner directly in the patient’s body with the potential to create life-changing therapeutics with demonstrated improved efficacy and reduced toxicities."

Key aspects of Cue Biopharma’s technologies discussed in the article include:

The Immuno-STAT platform enables development of first-in-class off-the-shelf biologic molecules designed to selectively engage and activate disease-relevant T cells via the T cell receptors (TCR), mimicking the natural immune process, through the presentation of complimentary and synergistic signals, or "cues." An Immuno-STAT is engineered to include:
A first signal, or "cue" involving the presentation of a targeted and specific epitope, via a major histocompatibility (MHC)-peptide complex, to T cell receptors, or TCRs, of disease-specific T cells, to selectively engage a repertoire of T cells relevant to a particular disease such as cancer.
A corresponding second signal, or "cue" comprising the immunostimulant IL-2 molecule engineered with particular modifications for activation and expansion of CD8+ cytotoxic T cells, the relevant type of T cells with cancer-killing activity and minimize off-target binding and activation.
The Immuno-STAT is constructed upon a portion of a human antibody (the "Fc portion") that serves as the molecule’s backbone or scaffold and provides manufacturability and structural stability.
Through this design, Immuno-STATs enable disease specificity, targeted selective activation of CD8+ T cells and a larger therapeutic window for IL-2 effectiveness.
Neo-STAT is a plug-and-play variation of the Immuno-STAT platform designed with an empty "pocket" for the peptide presentation signal, enabling easy integration of disease-specific antigens a-posteriori to target a variety of cancers and infectious diseases.
The modular Immuno-STAT framework is compatible with diverse co-modulators, including immuno-suppressive molecules, with potential to address a variety of autoimmune diseases.
Ken Pienta, M.D., acting chief medical officer of Cue Biopharma, added, "We have identified a potential solution to safety and scalability challenges based on natural signals governing T cell function: peptide-HLA and costimulatory ligands, embodied in the Immuno-STAT and Neo-STAT immunotherapy platforms. The versatility and modularity of the platform as described in the paper, in addition to the clinical data to date supports the premise that our approach could be the next-generation solution to utilizing IL-2 as a targeted and selective immune activator for treating multiple cancers."

Cue Biopharma’s lead Immuno-STAT asset, CUE-101 has already shown encouraging results as a monotherapy in a Phase 1 dose escalation trial in late stage second line and beyond patients with HPV+ recurrent/metastatic head and neck cancer, which included a confirmed partial response with approximately 65% durable and ongoing tumor reduction and eight confirmed stable disease responses, controlling tumor growth for at least 12 weeks.

The Company is preparing for an Investigational New Drug filing for their next Immuno-STAT clinical candidate, CUE-102, which targets Wilms Tumor 1 (WT1), expressed in numerous solid tumors and hematological cancers.

On September 28, 2021 GeoVax Labs, Inc. (Nasdaq: GOVX), a biotechnology company specializing in developing human vaccines and cancer immunotherapies, reported that it has entered into an Assignment and License Agreement (the "License") with PNP Therapeutics, Inc. ("PNP"), that grants GeoVax exclusive rights to develop and commercialize Gedeptin, a novel patented product for the treatment of solid tumors (Press release, PNP Therapeutics, SEP 28, 2021, View Source [SID1234597866]).

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The License provides exclusive worldwide rights to key intellectual property, including Gedeptin patents, knowhow, regulatory filings, clinical materials, and trademarks. The patent portfolio covering Gedeptin, was originally licensed from the University of Alabama at Birmingham (UAB) and Southern Research Institute (SRI) by PNP. Under the License, GeoVax will become the successor to PNP under its license agreement with UAB/SRI. Detailed financial terms of the transaction were not disclosed, but include a combination of upfront payments, milestone fees, and royalties on net sales.

A cycle of Gedeptin therapy consists of three intra-tumoral injections of Gedeptin over a two-day period followed by infusion of a prodrug, fludarabine phosphate, once a day for three days. A Phase 1 dose ranging study, evaluating the safety of a single cycle of Gedeptin therapy, found the therapy to be well tolerated, with evidence of a reduction in tumor size in patients with solid tumors.

A Phase 1/2 trial, evaluating the safety and efficacy of repeat cycles of Gedeptin therapy in patients with recurrent head and neck squamous cell carcinoma (HNSCC), with tumor(s) accessible for injection and no curable treatment options, is currently enrolling. The initial stage of the study is being funded by the FDA pursuant to its Orphan Products Clinical Trials Grants Program. The FDA has also granted Gedeptin orphan drug status for the intra-tumoral treatment of anatomically accessible oral and pharyngeal cancers, including cancers of the lip, tongue, gum, floor of mouth, salivary gland and other oral cavities.

The Gedeptin technology was developed with funding support from the National Cancer Institute of the National Institutes of Health. The License also grants GeoVax the rights to expand the use of Gedeptin to all human diseases and/or conditions including, but not limited to, other cancers.

David Dodd, GeoVax President and CEO, commented, "The signing of this license agreement is an important and exciting event for GeoVax and our stockholders, as it adds a clinical program in immuno-oncology to our pipeline, which is one of the primary focus areas for our company. The initial stage (10 patients) of the ongoing clinical trial for Gedeptin is being funded by the FDA pursuant to its Orphan Products Grants Program, with five patients having been enrolled to date. Our immediate objective will be to accelerate patient enrollment to complete this stage, then expand the trial to additional study sites and at least 25 patients in total. Based on PNP’s End-of-Phase-1 meeting with the FDA, we believe that a successful outcome from the expanded trial may lead to labelling discussions with the FDA at the end of the study."

Dodd added, "In addition to the immediate opportunity resulting from the existing clinical program, the license to the Gedeptin technology opens additional opportunities to potentially develop novel therapies for other indications. We also feel that potential synergies exist between the Gedeptin technology and our GV-MVAVLP platform related to immuno-oncology, providing further expanded opportunities for developing novel ### cancer immunotherapies that may benefit cancer patients across multiple cancers. As we continue to advance our programs such as MVA-VLP-MUC1, we will also evaluate synergistic opportunities between the two technology platforms."

In conclusion, Dodd commented, "Approximately one year ago, we achieved a critical strategic watershed with the successful recapitalization, financing and listing of GeoVax on the Nasdaq stock market. Since then, we have further strengthened the Company resources and status, including our ability to finance the Gedeptin transaction, including expansion and acceleration of the clinical trial using our current cash reserves. We have progressed our two core product development areas related to SARS-CoV-2 vaccines and immuno-oncology. Today’s announcement accelerates our progress within immuno-oncology, providing a pivotal clinical-stage status via the Gedeptin program. We similarly remain focused on accelerating progress related to our SARSCoV-2 vaccine and look forward to providing further updates soon."

Conference Call
Management will host a conference call at 4:30 p.m. ET on Wednesday, September 29, 2021 to review the transaction and discuss the Gedeptin technology. Following management’s formal remarks, there will be a question-and-answer session. Participants are asked to pre-register for the call via the following link: View Source The conference call will be available through a live webcast found here: View Source

A webcast replay of the call will be available via the same link as the live webcast approximately one hour after the end of the call through December 28, 2021. A telephonic replay of the call can be accessed by calling 1-877-344-7529 (domestic) or 1-412-317-0088 (international) and using access code 10160579. The telephonic replay will be available until October 13, 2021.

About the Gedeptin Technology Platform
Many common cancers (including prostate, breast, colon, lung, brain, melanoma, pancreas, ovarian, kidney) become untreatable despite the best medical intervention and the highest standard of care and are eventually fatal. Chemotherapeutic agents may be able to destroy these tumors, but many are much too toxic to administer systemically to already debilitated cancer patients. Most conventional anti-cancer drugs in use today derive their anti-tumor specificity from the ability to kill rapidly dividing cells. These drugs are suitable for systemic administration specifically because they are most toxic to cells that are dividing. However, many tumors such as head and neck squamous cell carcinoma (HNSCC) are resistant to treatment because they have a very low growth fraction (i.e., a relatively small percentage of tumor cells dividing at any particular point in time). Compounds toxic to non-proliferating cells generally are not used in the treatment of cancer, because most of the cells in a patient are not proliferating and such compounds have no selectivity when administered systemically.

Among the various gene therapy strategies for cancer treatment, GDEPT (Gene-Directed Enzyme Prodrug Therapy) has shown promise. In GDEPT a vector is used to selectively transduce tumor cells with a nonhuman gene, which expresses an enzyme that can convert a nontoxic prodrug into a very toxic antitumor compound. A prodrug is a pharmaceutical compound that remains inactive in its biochemical form until it reaches its target site, such as an organ or tissue, and then undergoes an immediate metabolic breakdown; it then releases the molecular compounds of the parent drug, or active ingredients, at the point of delivery. Because the nonhuman gene is only expressed in tumor tissue, the nontoxic prodrug is only activated in tumor tissue. Therefore, unlike conventional chemotherapy, GDEPT should result in selective killing of tumor cells with little or no systemic toxicity.

GDEPT strategies that produce potent cytotoxic agents (active against nonproliferating and proliferating tumor cells) and that have high bystander activity could have dramatic effects on the treatment of solid tumors. A ### bystander effect typically refers to the death, altered growth or damage of cells that have not directly received chemotherapy or irradiation. Earlier GDEPT approaches have had limited efficacy specifically because of poor bystander activity and inability to destroy non-proliferating tumor cells.

Gedeptin potentially overcomes previous GDEPT limitations and may serve as a robust platform for development in multiple indications. Gedeptin consists of a non-replicating adenoviral vector expressing an optimized E. coli purine nucleoside phosphorylase (E. coli PNP) that is injected intra-tumorally, and then followed by intravenous or intra-tumoral administration of a prodrug.

Among the prodrugs that have been evaluated for use with Gedeptin, fludarabine phosphate (Fludara) is of particular interest because (i) it is currently approved by the FDA for use in humans and (ii) it has demonstrated excellent in vivo antitumor activity in murine models when only 2-3% of tumor cells express E. coli PNP. Fludarabine is currently approved by the FDA to treat chronic lymphocytic leukemia, but has not been shown to be effective against other solid tumors. But when fludarabine is administered following Gedeptin, the combination exploits the selective expression of the E. coli PNP gene in tumor cells to utilize fludarabine phosphate as a prodrug, resulting in the localized production of fluoroadenine (F-Ade), a potent cytotoxic compound with pronounced antitumor activity.

Ongoing Phase 1/2 Clinical Trial – Currently, Gedeptin is in a Phase 1/2 clinical trial, being conducted at Stanford University in collaboration with Emory University. The trial design involves repeat administration using Gedeptin followed by systemic fludarabine, as a way to gain additional information prior to expansion towards a larger patient trial. The initial stage of the study (10 patients) is being funded by the FDA pursuant to its Orphan Products Grants Program. Five patients have been enrolled to date.

Orphan Drug Status – The FDA has granted orphan drug status to Gedeptin, for the intra-tumoral treatment of anatomically accessible oral and pharyngeal cancers, including cancers of the lip, tongue, gum, floor of mouth, salivary gland and other oral cavities. The orphan drug designation is awarded to drugs designed to treat a rare disease or condition that affects fewer than 200,000 people in the U.S., and it is applied specifically to novel therapeutics that could represent a major improvement in treatment. Orphan drug status provides regulatory incentives, reduced fees, and a more rapid review by the FDA, and stipulates that competing therapies can be blocked from the market for up to seven years. Additionally, this status qualifies the drug sponsor for various development incentives, including tax credits for qualified clinical testing.

On September 28, 2021 AmerisourceBergen (NYSE: ABC), Cardinal Health (NYSE: CAH) and McKesson (NYSE: MCK) reported that they have reached an agreement with the Cherokee Nation to pay approximately $75 million over 6.5 years to resolve opioid-related claims (Press release, Cardinal Health, SEP 28, 2021, View Source [SID1234591443]). This settlement was negotiated in connection with ongoing negotiations toward a broad resolution of opioid-related claims brought by Native American tribes that, as previously disclosed by the companies, are not covered by the ongoing settlement process involving state and local governmental entities. The companies view today’s settlement as an important step toward reaching a broader settlement with all federally recognized Native American tribes across the country.

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This settlement reflects an agreement of the Cherokee Nation to dismiss its ongoing lawsuit in exchange for the companies’ agreement that the Cherokee Nation will receive a settlement amount consistent with its anticipated allocation under a broader agreement with Native American tribes.

While the companies strongly dispute the allegations against them, they believe this resolution will allow the companies to focus their attention and resources on the safe and secure delivery of medications and therapies while delivering meaningful relief to affected communities, and will also support efforts to achieve a broad resolution with the remaining Native American tribes.

The companies remain deeply concerned about the impact the opioid epidemic is having on communities across the nation and remain committed to being part of the solution.

On September 28, 2021 ViiV Healthcare, the global specialist HIV company majority owned by GlaxoSmithKline (GSK), with Pfizer and Shionogi as shareholders, reported an exclusive collaboration and license agreement with Shionogi & Co. Ltd. (Shionogi) for S-365598, a third-generation investigational integrase strand transfer inhibitor (INSTI) with potential for use in ultra long-acting HIV regimens (regimens with dosing intervals of three months or longer) (Press release, GlaxoSmithKline, SEP 28, 2021, View Source [SID1234590619]).

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Under the terms of the agreement, ViiV Healthcare will make an upfront payment of £20 million to Shionogi, a £15 million payment for the achievement of a clinical development milestone and royalties on net sales. The royalty levels are aligned with those in Shionogi’s existing integrase inhibitor agreements with ViiV Healthcare. Shionogi will contribute to development costs up to an annual maximum.

Kimberly Smith, M.D., MPH, Head of Research & Development at ViiV Healthcare said: "Our 20-year relationship with Shionogi has been incredibly successful, producing what are arguably two of the most important HIV medicines of the last decade. Dolutegravir is now taken by 17 million people globally, and cabotegravir has allowed us to develop the first long-acting regimen for treatment. With today’s announcement about the in-licensing of a third integrase inhibitor from Shionogi, we will continue this collaboration and explore the potential of S-365598 to anchor ViiV Healthcare’s pipeline beyond 2030."

John Keller, Ph.D., Senior Executive Officer, Senior Vice President, Corporate Strategy Division at Shionogi said: "Many people living with HIV and those vulnerable to acquiring HIV have concerns about daily oral medication, such as the daily reminder of living with HIV, HIV status disclosure and consistency of adherence. Long-acting HIV medications have the potential to bring considerable benefit to these individuals. We are looking forward to continuing to work with ViiV to further advance this innovative approach to HIV therapies."

Preliminary data has shown that S-365598 has a high genetic barrier and a resistance profile that is distinct from that of dolutegravir and cabotegravir. Its long half-life may support its development as an ultra-long medicine that could be delivered with infrequent dosing of every three months or longer.

Preclinical studies are underway. ViiV Healthcare and Shionogi intend to initiate first time in human studies with S-365598 by 2023.

# # #

Important Safety Information for Cabenuva (cabotegravir 200 mg/mL; rilpivirine 300 mg/mL) extended release injectable suspensions

Cabenuva is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.

CONTRAINDICATIONS

Do not use Cabenuva in patients with previous hypersensitivity reaction to cabotegravir or rilpivirine.
Do not use Cabenuva in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort.
WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions:

Hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries.
Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with Cabenuva.
Discontinue Cabenuva immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Prescribe the oral lead-in prior to administration of Cabenuva to help identify patients who may be at risk of a hypersensitivity reaction.
Post-Injection Reactions:

Serious post-injection reactions (reported in less than 1% of subjects) were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events may have been associated with inadvertent (partial) intravenous administration and began to resolve within a few minutes after the injection.
Carefully follow the Instructions for Use when preparing and administering Cabenuva to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated.
Hepatotoxicity:

Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors.
Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations.
Monitoring of liver chemistries is recommended and treatment with Cabenuva should be discontinued if hepatotoxicity is suspected.
Depressive Disorders:

Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with Cabenuva or the individual products.
Promptly evaluate patients with depressive symptoms.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:

The concomitant use of Cabenuva and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions).
Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval. Cabenuva should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

Long-Acting Properties and Potential Associated Risks with Cabenuva:

Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance.
To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of Cabenuva. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.
ADVERSE REACTIONS

The most common adverse reactions (incidence ≥2%, all grades) with Cabenuva were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.
DRUG INTERACTIONS

Refer to the applicable full Prescribing Information for important drug interactions with Cabenuva, Vocabria, or rilpivirine.
Because Cabenuva is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine.
Cabenuva should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

USE IN SPECIFIC POPULATIONS

Pregnancy: There are insufficient human data on the use of Cabenuva during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using Cabenuva during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of Cabenuva. An Antiretroviral Pregnancy Registry has been established.
Lactation: The CDC recommends that HIV 1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Breastfeeding is also not recommended due to the potential for developing viral resistance in HIV-positive infants, adverse reactions in a breastfed infant, and detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of Cabenuva.

On September 28, 2021 NH TherAguix, a French biotechnology company specialising in the development of innovative nano medicines for the radiotherapy treatment of cancer indications, reported the launch of its initial public offering with a view to listing its shares on the Euronext Growth market (ISIN code: FR0013105954-ticker: ALNHT) (Press release, NH TherAguix, SEP 28, 2021, View Source [SID1234590544]). On 27 September 2021, the French financial markets authority (Autorité des Marchés Financiers-AMF) approved the Prospectus under number 21-416, comprising the Registration Document, approved on 10 September 2021 under number I.21-048, the supplement to this Registration Document approved on 27 September 2021 under number I.21-055, a Securities Note and a summary of the Prospectus (included in the Securities Note).

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Géraldine Le Duc, Chief Executive Officer of NH TherAguix, says: "NH TherAguix aims to demonstrate that its candidate drug AGuIX increases the effectiveness of radiotherapy on solid tumours, while sparing the surrounding healthy tissues. It offers new hope for cancer patients and our ambition is to make AGuIX the new standard of care in the treatment of certain cancers with radiotherapy. To do this, we have developed AGuIX so that it can be integrated into all current care protocols, without changing patient treatment. The indications that we are primarily targeting include pancreatic cancer, glioblastoma, the most comment brain cancer found in adults, and brain metastases. This planned IPO will allow us, on the one hand, to consolidate the Company’s financial position and, on the other, to obtain additional resources to be able pursue the development of the candidate drug AGuIX, and more specifically to develop the current pipeline of clinical trials (covering in particular glioblastoma, pancreatic cancer and brain metastases) with a view to registration trial, for which the Company would act as sponsor. I hope I can count on the support of many institutional and retail investors in this human and entrepreneurial adventure." Press Release Should not be published, transmitted or distributed directly or indirectly in the United States of America, Canada, Japan or Australia 2 Pushing the current boundaries of radiotherapy In the fight against cancer, radiotherapy is one of the standard care treatments. 60% of patients with cancer are treated with radiotherapy during their care pathway.

However, despite advances in technology and the continuous improvement of equipment, radiotherapy has limitations due to the harmful effects it causes on healthy tissue close to the tumour. These side effects limit the effectiveness of certain treatments and sometimes make radiotherapy unsuitable for certain forms of cancer. A theranostic1 approach for precision radiotherapy Increasing the x-ray dose differential between the tumour and surrounding healthy tissue is now the most promising way of improving radiotherapy.

Based on this observation, NH TherAguix has developed an innovative theranostic1 approach in nanomedicine: AGuIX. Designed to be able to increase the dose differential between the tumour and healthy tissues and therefore to increase the efficacy of radiation therapy, AGuIX also allows more accurate imaging guidance after targeting the tumour. The combination of these three properties (targeting, imaging and treatment) paves the way for a new generation of precision radiotherapy.

The first "triple action" candidate drug By injecting a single dose, AGuIX works in three complementary ways:
1. Targeting: Nanoparticles are injected intravenously. Thanks to their size of 5 nanometers, they accumulate naturally and exclusively in the tumour through a biodistribution process (effect known as EPR2).
2. Imaging: The presence of gadolinium atoms in the structure of AGuIX ensures that the tumour is clearly visible via magnetic resonance imaging prior to radiotherapy, allowing the tumour to be delineated in order to calibrate radiation therapy.
3. Treatment: Its radiosensitising properties enable AGuIX to amplify the effect of radiation directed against the tumour through a physical interaction. By creating a dose differential between the cancer and adjacent tissues, the radiation therapy could become more effective. A candidate drug adapted to the patient care pathway Intravenous administration of AGuIX is a key component of its therapeutic effectiveness as it makes it easy to use by healthcare staff. It does not disrupt the treatment pathway, and does not require any specific equipment or training. It is also possible to combine

AGuIX with all current and future radiotherapy technologies.
1 Theranostics: therapeutic approach combined with better diagnosis.
2 Enhanced Permeability Retention effect: nanoparticles tend to accumulate more in the tumour than in healthy tissues, mainly due to 2 biological phenomena: abnormal blood vessel development and inefficiency of lymphatic drainage in cancerous tissues. Press Release Should not be published, transmitted or distributed directly or indirectly in the United States of America, Canada, Japan or Australia
3 Strong proof of concept The first study in humans was conducted in the Phase 1b trial on brain metastases in 15 patients, NANORAD 1, which first helped to established the absence of toxicity and adverse effects of AGuIX.

In addition to the safety parameters, this study demonstrated a clinical benefit with encouraging overall survival rates and confirmed the triple effect of AGuIX after injection (targeting, imaging and treatment). A dose effect has also been highlighted: the higher the concentration of AGuIX in brain metastases, the lower their size and therefore the better their response to treatment.3 Preliminary observations of the ongoing NANORAD 2, Phase 2 trial on brain metastases show tolerance and contrast entirely consistent with the Phase 1 trial results. It also seems that the activity signals of AGuIX already cited, namely a radiosensitisation response related to improved control of tumour volume and survival, can be observed here. These very preliminary observations reveal a trend that needs to be confirmed or invalidated based on the existence of the control arm and the statistical strength of the trial if sufficient. A potential pan-cancer treatment deployed through 8 Phase 1 and 2 clinical trials, 3 of which are already recruiting, 4 of which have been authorised by health authorities and one of which is being prepared The properties of AGuIX show pan-cancer potential: intravenous injection combined with the ability of AGuIX to accurately target the tumour enables the treatment of cancers that are difficult to access by intratumoral injection. At this stage, all injected tumours have been visible via MRI (49 patients). Markus Loeffler, NH TherAguix Medical Director, comments: "The results of the Phase 1 study are very encouraging. NH TherAguix has now entered Phase 2 with 2 clinical trials focusing on radiotherapy for brain metastases, either by whole brain radiotherapy (NANORAD 2), or as a complementary treatment by radiosurgery (NANOBRAINMETS), and also has a Phase 1 trial on advanced cervical cancer (NANOCOL).

The launch of other trials in Europe and the United States, in partnership with internationally renowned cancer research institutes, is a very important strategic step for NH TherAguix." 3Targeting brain metastases with ultrasmall theranostic nanoparticles, a first-in-human trial from an MRI perspective. Verry C et al. Science Advances. 2020 Theranostic AGuIX nanoparticles as radiosensitizer: A phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial) Verry C. et al. Radiotherapy & Oncology, 2021 Press Release Should not be published, transmitted or distributed directly or indirectly in the United States of America, Canada, Japan or Australia 4 By the end of 2021, AGuIX technology should be in use in 7 Phase 1 and 2 clinical trials, 3 of which are already recruiting and 4 of which have been authorised by health authorities: *ODD (Orphan Drug Designation): orphan candidate drug status obtained in the United States, allowing for fast track recording in case of conclusive outcomes.

Clinical Development Strategy The clinical development strategy of AGuIX aims to exploit its pan-cancer potential with the objective of recording as quickly as possible primary and orphan cancers such as pancreatic cancer or glioblastoma, for which the therapeutic arsenal is very limited and which represent a significant market opportunity. For these indications, the Company operates in partnership with recognised institutes such as Dana-Farber Cancer Institute and Harvard. The Company is also targeting a broader market, namely the treatment of brain metastases, an indication in which the Company has already acquired results and the potential of which is significant due to its impact, and in which the number of competitors is limited.

Finally, the Company is considering the development of AGuIX to treat other indications. It is therefore promoting the implementation of clinical trials funded by research grants as part of academic collaborations to enable it to collect clinical and scientific data while preserving its financial resources. Press Release Should not be published, transmitted or distributed directly or indirectly in the United States of America, Canada, Japan or Australia 5 Financial and industrial support In 2019, the company experienced strong growth, having raised Series A funding of €12.3 million from recognised venture capital funds (BPI Innobio2, Arbevel, Omnes and Supernova). Thanks to this funding, the Company was able to launch its Phase 2 clinical trials and fund the scaling of production of its experimental drug, in partnership with Sanofi, the laboratory that produces the AGuIX nanoparticle. Offering eligible for PEA and PEA-PME equity savings plans NH TherAguix complies with the eligibility criteria for PEA-PME equity savings plans specified by the provisions of Articles L.-221-32-2 and D.221-113-5 et seq. of the French Monetary and Financial Code. As a result, NH TherAguix’s shares can be fully integrated into equity savings plans (PEAs) as well as PEA-PME accounts which enjoy the same tax benefits as traditional PEAs*.

Availability of the Prospectus Copies of the Prospectus approved by the AMF on 27 September 2021 under number 21-416 are available free of charge upon request from the Company and can also be consulted on the websites of the AMF (View Source) and NH TherAguix (View Source). Approval of the Prospectus should not be considered as a favourable opinion on the securities offered or admitted for trading on the Euronext Growth market in Paris. Risk Factors The risks associated with pursuing the effective progress of AGuIX’s clinical development, and more generally the risk factors to which the Company is exposed are presented in Chapter 3 "Risk Factors" of the Registration Document and in Section 3 "Risk factors related to the Offering" in the Securities Note. The occurrence of one or more of these risks is liable to have a significant adverse impact on the activities, assets, financial position, results or outlook of NH TherAguix, as well as on the market price of the Company’s shares.

Financial intermediaries and advisers Global Coordinator and Joint Bookrunner Joint Bookrunner Financial Communication Agency Legal counsel Statutory Auditors Statutory Auditors Press Release Should not be published, transmitted or distributed directly or indirectly in the United States of America, Canada, Japan or Australia

6 MAIN TERMS OF THE TRANSACTION ▪ SHARE CAPITAL BEFORE THE ISSUE A public limited company (société anonyme) with a board of directors, with share capital of €244,081.00 divided into 6,102,025 shares with a par value of €0.04 each.
▪ CHARACTERISTICS OF THE SHARES
• Title: NH TherAguix
• Ticker: ALNHT
• ISIN: FR0013105954
• Listing market: Euronext Growth Paris
• ICB classification: 20103010-Biotechnology
• LEI: 9695007Z8UJ5AFRZQN66
• Eligible for the PME-ETI equity savings plan
▪ INDICATIVE PRICE RANGE Between €15.50 and €18.90 per new share. This information is provided for information purposes only and is in no way indicative of the price of the Offering, which may be set outside this indicative range. ▪ INITIAL SIZE OF THE OFFERING The Offering will be made by placing on the market 1,744,187 new shares to be issued, which may be increased to 2,005,815 new shares in the event of full exercise of the extension clause and 300,872 additional new shares in the event of full exercise of the overallotment option, i.e. a maximum of 2,306,687 shares offered in the event of full exercise of the extension clause and the overallotment option.

▪ GROSS TRANSACTION AMOUNT Approximately €30 million, which may be increased to approximately €34.5 million in the event of full exercise of the extension clause and approximately €39.7 million in the event of full exercise of both the extension clause and the overallotment option (based on the midpoint of the indicative price range of the Offering, i.e. €17.20). ▪ NET PROCEEDS FROM THE OFFERING Approximately €27.2 million, which may be increased to approximately €31.4 million in the event of full exercise of the extension clause and approximately €36.3 million in the event of full exercise of both the extension clause and the overallotment option (based on the midpoint of the indicative price range of the Offering, i.e. €17.20). Press Release Should not be published, transmitted or distributed directly or indirectly in the United States of America, Canada, Japan or Australia

7 ▪ STRUCTURE OF THE OFFERING The offered shares will be distributed as part of a global offering (the "Offering"), comprising:
• An offering to the public in France in the form of an open-price offering, mainly intended for private individuals (the "Open-Price Offering" or "OPO"), where: o the orders will be broken down according to the number of shares requested: A1 order fraction (from 1 share up to 250 shares) and A2 order fraction (over 250 shares); o the A1 order fractions will receive preferential treatment relative to the A2 order fractions in the event that all orders cannot not be entirely satisfied.
• A global placement mainly intended for institutional investors (the "Global Placement"), comprising: o a placement in France; o an international private placement in certain countries, excluding in particular the United States of America, Japan, Canada and Australia; and o a private placement in the United States for a limited number of qualified institutional buyers as defined in Rule 144A of the U.S. Securities Act of 1933 (as amended) (the "Securities Act"), in the context of the exemption of private placements from the registration provisions pursuant to Article 4(a)(2) of the Securities Act. If permitted by the request expressed under the OPO, the number of shares allocated in response to orders issued under the OPO will be at least equal to 10% of the number of shares offered under the Offering (before any exercise of the extension clause and the overallotment option).

▪ LOCK-UP COMMITMENTS AND CONSERVATION Company lock-up agreement: 180 calendar days following the settlement/delivery date of the Offering, subject to certain exceptions. Commitment by the Company’s shareholders to hold on to their shares: all shareholders and holders of securities giving access to the Company’s share capital shall make a commitment to the joint bookrunners to conserve the shares they hold on the date on which the Offering Price is set for a period of 270 calendar days following the settlement-delivery date of the Offering, subject to certain usual exceptions.

▪ SUBSCRIPTION COMMITMENTS FPCI InnoBio 2, represented by Bpifrance Investissement, FCPI Arbevel Life Sciences Crossover I, represented by Financière Arbevel, and FCPI Supernova 2, represented by Supernova Invest, have each committed to place a subscription order in the order book for a maximum amount of €3.00 million, €2.35 million and €1.50 million respectively. In addition, Guerbet, a French company with international expertise in medical imaging (diagnostic and interventional) and listed on Euronext Paris, has made a commitment to place an order of €3.00 million in the order book. These orders, which therefore represent 32.8% of the gross proceeds of the Offering (if the Offering is 100% subscribed and excluding the exercise of the extension clause and the overallotment option) are intended to be served in priority and in their entirety, subject to reduction in accordance with usual allocation principles (mainly if the subscriptions received are way over the number of shares offered).

Press Release Should not be published, transmitted or distributed directly or indirectly in the United States of America, Canada, Japan or Australia 8 Guerbet’s investment comes as both companies have started to work together on artificial intelligence for clinical trials on pancreatic cancer and glioblastoma, as developed by the Company. Last July, the Company and Guerbet tendered together for State funding (as an Important Project of Common European Interest (IPCEI)) in this area. Regardless of the (limited) chances of obtaining such funding, the agreement signed on 23 September 2021 on Guerbet’s subscription commitment suggests that the two companies will discuss the scope of collaboration work on the AGuIX platform and will subsequently negotiate a collaboration agreement to that effect in good faith.