On June 12, 2023 RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, reported its first quarter 2023 financial results and operational highlights (Press release, RedHill Biopharma, JUN 12, 2023, View Source [SID1234632667]).

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Dror Ben-Asher, RedHill’s Chief Executive Officer, said: "2023 has commenced with purpose and clarity, with a streamlined cost-base and without the restrictive burden of debt. Commercial focus, once the Movantik transition period is complete, will see all efforts aligning to maximize Talicia and potentially secure additional revenue-generating products to further augment our commercial portfolio. There is equal clarity on the R&D front with full focus being applied to opaganib, RHB-107 and RHB-102. Opaganib’s current development for Acute Radiation Syndrome is under the guidance and full financial support of the NIH Radiation and Nuclear Countermeasures Program product development contract, while RHB-107’s late-stage development for non-hospitalized COVID-19 will benefit from the resources we are able to redirect from the terminated RHB-204 Phase 3 study. Additional antiviral research with NIH and the US Army also continues for both product candidates for pandemic preparedness purposes."
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1 Including cash, cash equivalents, short-term bank deposits and restricted cash.
2 Including all principal, interest, revenue interest, prepayment premiums and exit fees under the Credit Agreement between RedHill’s U.S. subsidiary RedHill Biopharma Inc. and HCR Collateral Management LLC ("HCR"). Remaining pre-closing liabilities related to Movantik as of March 31, 2023, estimated at $27 million.
Financial results for the three months ended March 31, 2023 (Unaudited)3

Net Revenues for the first quarter of 2023 were $3.6 million, as compared to $12.8 million for the fourth quarter of 2022. The decrease is primarily related to the divestiture of Movantik, resulting in the discontinuation of revenue recognition from this product starting from February 2, 2023. Talicia net revenues for the first quarter of 2023 were $3.4 million, as compared to $2.2 million for the fourth quarter of 2022, primarily due to an increase of 20% in units sold.

Cost of Revenues for the first quarter of 2023 were $1.6 million, as compared to $8.6 million for the fourth quarter of 2022. This decrease can be primarily attributed to the divestiture of Movantik. As a result of this divestiture, both the recognition of revenue and the associated cost of revenues for this product were discontinued starting from February 2, 2023. Additionally, the amortization of the intangible asset related to Movantik was also discontinued as of that date.

Gross Profit for the first quarter of 2023 was $2.0 million, as compared to $4.2 million for the fourth quarter of 2022, in line with the decrease in Net Revenues and Cost of Revenues as explained above and primarily attributed to the divestiture of Movantik.

Research and Development Expenses for the first quarter of 2023 were $1.1 million, consistent with the fourth quarter of 2022.

Selling, Marketing and General and Administrative Expenses for the first quarter of 2023 were $10.9 million, as compared to $13.0 million for the fourth quarter of 2022. The difference was primarily attributable to the successful ongoing cost-reduction measures.

Other Income for the first quarter of 2023 was $39.1 million, as compared to no other income recognized for the fourth quarter of 2022. The other income was comprised of (i) $35.5 million from the sale of Movantik, calculated as the difference between the fair value of the rights and the carrying amount of this asset; and (ii) from transitional services fees provided to the buyer of Movantik.

Operating Income for the first quarter of 2023 was $29.1 million, as compared to an operating loss of $9.9 million for the fourth quarter of 2022, primarily attributed to the changes resulting from the sale of Movantik, as detailed above.

Financial Income, net for the first quarter of 2023 was $21.2 million, as compared to Financial Income, net of $6.2 million for the fourth quarter of 2022. The income recognized in the first quarter of 2023 was primarily related to gain resulting from the extinguishment of the HCR Collateral Management LLC ("HCR") debt in exchange for the transfer of rights to Movantik, calculated as the difference between the carrying amount of the financial liability and the fair value of the rights transferred.
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3 All financial highlights are approximate and are rounded to the nearest hundreds of thousands.
Net Income for the first quarter of 2023 was $50.2 million, as compared to Net Loss of $3.7 million for the fourth quarter of 2022, primarily attributed to the changes resulting from the sale of Movantik, as detailed above.

Total Assets as of March 31, 2023, were $58.8 million, as compared to $158.9 million as of December 31, 2022. The decrease was primarily attributable to the sale of Movantik, resulting in the transfer of the rights to Movantik, as well as to a significant decrease in the Trade Receivables balance following the sale of Movantik.

Total Liabilities as of March 31, 2023, were $56.8 million, as compared to $207.3 million as of December 31, 2022. This decrease was primarily due to the extinguishment of HCR debt in exchange for the transfer of Movantik rights, assumption of certain liabilities by HCR, and payments made towards pre-closing liabilities related to Movantik.

Net Cash Used in Operating Activities for the first quarter of 2023 was $7.2 million, as compared to $2.4 million for the fourth quarter of 2022. The difference was primarily attributed to the payments made towards the pre-closing liabilities related to Movantik.

Net Cash Provided by Financing Activities for the first quarter of 2023 was $4.8 million comprised primarily of prepayment from the registered direct offering that closed on April 3, 2023, and the decrease in restricted cash offset by payment in respect of intangible assets purchases.

Cash Balance as of March 31, 2023, was $28.8 million4.

Business updates

On May 15, 2023, the Company announced that it had received a written notification from the Nasdaq Stock Market LLC ("Nasdaq") dated May 9, 2023, indicating that the Company is not in compliance with the minimum Market Value of Publicly Held Shares ("MVPHS") set forth in the Nasdaq Rules for continued Nasdaq listing. Nasdaq Listing Rule 5450(b)(3)(C) requires companies to maintain a minimum MVPHS of US$15 million, and Listing Rule 5810(c)(3)(D) provides that a failure to meet the MVPHS requirement exists if the deficiency continues for a period of 30 consecutive business days. Pursuant to Nasdaq Listing Rule 5810(c)(3)(D), the Company has a compliance period of 180 calendar days (or until November 6, 2023) to regain compliance. If at any time during this compliance period the Company’s MVPHS closes at US$15 million or more for a minimum of ten consecutive business days, Nasdaq will notify the Company that it has achieved compliance with the MVPHS requirement, and the MVPHS matter will be closed. In the event the Company does not regain compliance with Rule 5450(b)(3)(C) prior to the expiration of the compliance period, it will receive written notification that its securities are subject to delisting. Alternatively, the Company may consider applying to transfer its securities to the Nasdaq Capital Market. This notification does not impact the listing and trading of the Company’s securities at this time.
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4 Including cash, cash equivalents, short-term bank deposits and restricted cash.
On April 11, 2023, the Company announced that it had received confirmation from Nasdaq that it had regained compliance with the minimum bid price requirement under Nasdaq Listing Rule 5450(a)(1) for continued Nasdaq listing. To regain compliance with Nasdaq Listing Rule 5450(a)(1), the Company was required to maintain a minimum closing bid price of $1.00 or more for at least 10 consecutive trading days, which was achieved on April 5, 2023. Listing compliance follows the Company’s implementation of a ratio change of the Company’s American Depositary Shares ("ADSs") to its non-traded ordinary shares from the previous ratio of one (1) ADS representing ten (10) ordinary shares to a new ratio of one (1) ADS representing four hundred (400) ordinary shares, which the Company announced on March 16, 2023. The ratio change came into effect on March 23, 2023, and the Company’s ADSs continue to be traded on Nasdaq under the symbol "RDHL" with a new CUSIP Number 757468202.

On April 3, 2023, the Company announced the closing of a $6 million registered direct offering for the purchase and sale of 1,500,000 of the Company’s ADSs (or ADS equivalents), Series A warrants to purchase up to an aggregate of 1,500,000 ADSs and Series B warrants to purchase up to an aggregate of 1,500,000 ADSs. The Series A warrants have an exercise price of $4.75 per ADS, are exercisable immediately and have a term of five years following issuance, and the Series B warrants have an exercise price of $4.00 per ADS, are exercisable immediately and have a term of nine months following issuance. 811,000 ADSs underlying pre-funded warrants purchased at the registered direct offering were exercised following the closing of the offering, announced April 3, 2023. The Company expects to recognize $1.1 million as a financial expense in the second quarter of 2023 due to the difference between the fair value of the warrants arising from the registered direct offering to the transaction price.

On February 6, 2023, the Company announced the extinguishment of all RedHill’s debt obligations (including all principal, interest, revenue interest, prepayment premiums and exit fees) under the Credit Agreement between RedHill’s U.S. subsidiary, RedHill Biopharma Inc., and HCR, announced February 25, 2020, as amended, in exchange for the transfer of its rights in Movantik (naloxegol) to Movantik Acquisition Co., an affiliate of HCR. HCR assumed substantially all post-closing liabilities, and RedHill retained substantially all pre-closing liabilities relating to Movantik. As part of the parties’ arrangement, and to ensure continuous patient care, RedHill provides HCR with transition services for up to 12 months, paid for by HCR. HCR will retain security interests in certain RedHill assets until substantially all pre-closing liabilities relating to Movantik have been paid or other specific conditions are met.

In the first quarter of 2023, the Company sold 2,625 ADSs through its at-the-market facility at an average price of $7.34 per ADS, for aggregate net proceeds of approximately $20,000.
RedHill continues its litigation against Kukbo Co. Ltd. ("Kukbo") which was filed on September 2022 as a result of Kukbo’s default in delivering to RedHill a total of $6.5 million under the Subscription Agreement, dated October 25, 2021 and the Exclusive License Agreement, dated March 14, 2022. Following a recent court decision on RedHill’s motion to dismiss Kukbo’s counterclaims, which accepted certain claims of RedHill and rejected others, RedHill filed a motion to reargue (a motion to clarify and correct some of the court’s rulings). RedHill further plans to continue to rigorously pursue the Kukbo litigation.

RedHill is actively pursuing strategic business development transactions, including potential in-licensing revenue-generating assets in the U.S. and out-licensing certain RedHill development pipeline assets.

Commercial Highlights

Talicia (omeprazole magnesium, amoxicillin and rifabutin)5

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Q1/23 saw Talicia recording a 9.6% increase in new prescriptions compared to the same period last year, maintaining its place as the leading prescribed branded H. pylori therapy by U.S. gastroenterologists6.

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On May 9, 2023, the Company announced new Talicia PBPK modeling data, published in AP&T Journal7, showing that generically substituted regimens are non-bioequivalent to Talicia. Separately, new Talicia PBPK modeling data, presented at Digestive Diseases Week (DDW) 2023, supports bioequivalence between TID and Q8H dosing regimens for Helicobacter pylori (H. pylori) eradication therapy; TID dosing is thought to promote patient adherence without impacting efficacy.

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On March 21, 2023, the Company announced the establishment of a warranty program for Talicia, in which RedHill committed to reimburse patient out of pocket costs should Talicia not work. This warranty commitment extends to all commercially insured and non-insured Talicia patients who complete the full 14-day treatment course and whose infection is not eradicated based on post-treatment confirmation testing8. It is believed that this is the first time a warranty program has been offered for a widespread community (non-hospital) treated condition, lowering the bar for patient access.

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Total Talicia coverage stood at more than 202 million American lives as of March 31, 2023.
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5 Talicia (omeprazole magnesium, amoxicillin and rifabutin) is indicated for the treatment of H. pylori infection in adults. For full prescribing information see: www.Talicia.com.
6 IQVIA XPO Data on file
7 Howden et al. Physiologically based pharmacokinetic modelling to predict intragastric rifabutin concentrations in the treatment of Helicobacter pylori infection. Alimentary Pharmacology and Therapeutics, April 2023. View Source
8 Talicia Warranty Program eligibility: View Source
Aemcolo (rifamycin)9

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On December 5, 2022, the Company announced that the FDA Exclusivity Board has granted Aemcolo five years’ exclusivity under the FDA’s Qualified Infectious Disease Product (QIDP) designation in addition to the five years NCE data exclusivity, extending regulatory exclusivity through to 2028.

Movantik (naloxegol)10

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On February 6, 2023, the ownership of Movantik was transitioned to Movantik Acquisition Co., an affiliate of HCR, in exchange for extinguishment of all RedHill’s debt obligations with HCR. Movantik is no longer a RedHill product. Revenues for Movantik were recorded up to and including February 1, 2023.

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As part of the agreement, and to ensure continuous patient care, RedHill is providing HCR with transition services for up to 12 months, paid for by HCR.

R&D Highlights

Opaganib (ABC294640)11 – A novel broad-acting, host-directed oral antiviral targeting radioprotection, COVID-19, other viruses as part of a pandemic preparedness approach, inflammatory indications and oncology.

Nuclear Medical Countermeasures (Acute Radiation Syndrome):

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On February 28, 2023, the Company announced that the Radiation and Nuclear Countermeasures Program (RNCP), of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, has selected opaganib for the nuclear medical countermeasures product development pipeline as a potential treatment for Acute Radiation Syndrome (ARS). As part of this collaboration, contractors directed and supported by the RNCP will undertake studies, designed in collaboration with RedHill, to test opaganib in established ARS models. This follows the February 15, 2023, announcement that the FDA provided guidance on the use of the Animal Rule for opaganib’s developmental pathway for Acute Radiation Syndrome (ARS), utilizing pivotal animal model efficacy studies instead of human clinical trials. Sponsors of approved medical countermeasures are eligible for a Priority Review Voucher. These announcements followed publication of data from eight U.S. government-funded in vivo studies, and additional experiments, indicating that opaganib was associated with:

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Protection of normal tissue, including gastrointestinal, from radiation damage due to ionizing radiation exposure or cancer radiotherapy.

o
Improvement of antitumor activity, response to chemoradiation, and enhancement of tolerability and survival.

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Additional collaboration discussions with U.S. and other governments are ongoing.
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9 Aemcolo (rifamycin) is indicated for the treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli in adults. For full prescribing information see: www.aemcolo.com.
10 Movantik (naloxegol) is indicated for opioid-induced constipation (OIC). Full prescribing information see: www.movantik.com.
11 Opaganib is an investigational new drug, not available for commercial distribution.
Pandemic preparedness and oncology:

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Preclinical development of opaganib, in collaboration with the US Army and NIAID, for various antiviral indications is ongoing.

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On May 1, 2023, the Company announced that the U.S. Patent and Trademark Office (USPTO) had granted a new patent for opaganib in respect to combination compositions for treatment of cancer, extending protection to October 2036.

RHB-107 (upamostat)12 – A novel broad-acting, host-directed oral antiviral targeting COVID-19, other viruses as part of a pandemic preparedness approach, inflammatory and oncology indications.

Outpatient treatment of COVID-19:

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On January 3, 2023, the Company announced publication of positive data from a Phase 2 study of once-daily oral investigational RHB-107 (upamostat) in non-hospitalized symptomatic COVID-19 patients, in the peer-reviewed International Journal of Infectious Diseases13. The study showed that RHB-107 successfully met the primary endpoint of safety and tolerability and delivered promising efficacy results, despite the small number of patients in each treatment group, including faster recovery from severe COVID-19 symptoms and 100% reduction in hospitalization due to COVID-19.

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Discussions are ongoing for external non-dilutive funding for additional late-stage COVID-19 clinical development.

Pandemic preparedness / additional viral indications:

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RHB-107 is also the subject of several cooperative research projects with government and non-government bodies, evaluating RHB-107 against multiple viral targets, including influenza and Ebola (amongst others).

RHB-102 (BEKINDA) – Oncology Support

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On May 1, 2023, the Company announced that the European Patent Office granted RHB-102 (BEKINDA), a 24-hr bimodal release, once-daily oral tablet formulation of ondansetron, a patent covering antiemetic extended-release solid dosage forms for the prevention of nausea and vomiting (CINV/RINV). The patent provides the potential for UK and EU protection of RHB-102 to March 2034.

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On February 16, 2023, the Company announced that it held a positive pre-Marketing Authorisation Application meeting with the UK Medicines & Healthcare products Regulatory Agency (MHRA) with regard to seeking marketing approval for RHB-102 (BEKINDA) for oncology support (management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, also referred to as CINV and RINV).

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Discussions for potential commercialization partners are ongoing.

RHB-204 – Pulmonary Nontuberculous Mycobacteria (NTM) Disease14 (NTM)

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On May 22, 2023, the Company announced the termination of RHB-204’s U.S. Phase 3 study for non-tuberculosis mycobacteria (NTM) disease due to a very low accrual rate. This decision is intended to enable the Company to better focus its resources on key pipeline catalysts and revenue-generating product acquisition, while searching for out-licensing partners for RHB-204.
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14 RHB-204 is an investigational new drug, not available for commercial distribution.

On June 12, 2023 Marker Therapeutics, Inc. (Nasdaq: MRKR), a clinical-stage immuno-oncology company focusing on developing next-generation T cell-based immunotherapies for the treatment of hematological malignancies and solid tumor indications, reported that the first patient has been treated in the company sponsored Phase 1 multicenter APOLLO trial investigating MT-601, a multi-tumor-associated antigen (multiTAA)-specific T cell product targeting six antigens, for the treatment of patients with lymphoma who have failed or are ineligible to receive anti-CD19 CAR T cell treatment (Press release, Marker Therapeutics, JUN 12, 2023, View Source [SID1234632664]).

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Adoptive T cell transfer, such as genetically modified T cells expressing anti-CD19 chimeric antigen receptors (CARs) targeting CD19 antigens, is a therapeutic modality that has recently demonstrated impressive clinical impact in patients with large B-cell malignancies who have failed more than two lines of treatment. Administration of anti-CD19 CAR T cells to patients with relapsed/refractory B-cell lymphomas have been a transformative treatment paradigm because of their significant benefit relative to the standard of care. However, for various reasons, including low antigen levels and loss of CD19 antigen expression, anti-CD19 CAR T cell therapy is associated with relapse rates of up to 60%, within one year (Chong et al, N Engl J Med, 2021). In addition, a number of patients with relapsed/refractory B-cell lymphomas are ineligible for anti-CD19 CAR T cell therapy due to the associated toxicities.

A recent Phase 1 study conducted by Baylor College of Medicine (TACTAL) investigated the safety and efficacy of a multiTAA-specific T cell product that recognizes five tumor antigens in both Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (Vasileiou et al, J Clin Oncol, 2021). Treatment with this multiTAA-specific T cell product resulted in positive patient outcomes with some patients remaining in complete remission at the 72 months follow-up.

Marker is developing MT-601, an autologous T cell product that is directed against six tumor associated antigens for the treatment of patients with relapsed/refractory lymphoma who are either ineligible to receive or have failed anti-CD19 CAR T cell therapy. Given the positive TACTAL trial results, which targeted five tumor associated antigens, Marker believes broadening its multiTAA-specific T cell product to target six antigens could result in better and more durable responses due to its ability to overcome antigen loss by targeting more than one antigen.

The recent press release issued by Marker on May 31, 2023, referenced in vitro nonclinical data indicating that MT-601 prevented growth of lymphoma cells regardless of CD19 expression and prevented growth of CD19 expressing lymphoma cells that had become resistant to CAR T infusion. These data demonstrate the therapeutic potential of MT-601.

The APOLLO trial (clinicaltrials.gov Identifier: NCT05798897) sponsored by Marker is assessing MT-601 in patients with lymphoma who have either relapsed after anti-CD19 CAR T cell therapy or were ineligible to receive it. The primary objective of this exploratory Phase 1 clinical trial is to evaluate the optimum dose, safety, and preliminary efficacy of MT-601 in patients with various lymphoma subtypes. Data from the APOLLO trial will guide Marker Therapeutics on the future development of MT-601.

The first patient in the APOLLO trial recently received MT-601 at the 200 million cell dose level. This patient was monitored for 18 days after being dosed and showed no treatment-related adverse events, indicating that the therapy was well tolerated. This observation is consistent with the favorable safety profile and tolerability previously reported for lymphoma patients in the TACTAL study. Under the APOLLO trial, eight clinical sites across the United States will cumulatively enroll up to 30 patients during the dose escalation phase.

"The initiation of clinical treatment under the APOLLO trial represents not just a major achievement for our team at Marker, but a beacon of hope for countless individuals with lymphoma who are confronting the reality of disease progression," said Monic Stuart, M.D., Chief Medical Officer of Marker Therapeutics. "Our vision with MT-601 is to fundamentally change the treatment landscape of lymphoma, providing a solution that could drastically enhance the lives of patients."

"Phase 1 of the clinical trial is a critical period," continued Dr. Stuart. "This stage will provide us with key insights into the safety, optimal dosage range, and initial efficacy of MT-601. The collected data will serve as a foundation for refining our understanding of the performance of MT-601 and its potential outcomes in patients with lymphoma who have relapsed after anti-CD19 CAR T therapy."

"We are grateful to our dedicated team of scientists, clinicians, and trial participants who have made this significant step possible," said Juan F. Vera, M.D., Chief Executive Officer of Marker Therapeutics. "Behind this milestone is an extensive body of research and a rigorous development process. The initiation of this clinical trial is rooted in a set of scientific data, which has shown compelling signs of potential clinical impact of MT-601 in attacking anti-CD19 CAR T refractory lymphoma cells. These promising nonclinical results, together with previous clinical observations from the TACTAL study, have given us confidence in the potential for multiTAA-specific T cell therapies to target lymphoma cells."

"The initiation of clinical treatment under the Phase 1 trial of MT-601 is a major step in our mission to bring forward transformative advancements in lymphoma treatment, with the goal of significantly improving patient outcomes. We are committed to diligently monitoring and analyzing the data from this Phase 1 clinical trial to ensure we continue making informed decisions that prioritize patient safety and therapeutic effectiveness," concluded Dr. Vera.

About multiTAA-specific T cells

The multi-tumor associated antigen (multiTAA)-specific T cell platform is a novel, non-genetically modified cell therapy approach that selectively expands tumor-specific T cells from a patient’s blood capable of recognizing a broad range of tumor antigens. Clinical trials that enrolled more than 180 patients with various hematological malignancies and solid tumors showed that the multiTAA-specific T cell product was well tolerated, demonstrated durable clinical responses, and consistent epitope spreading. The latter is typically not observed with other T cell therapies and enables the patient’s own T cells to expand, potentially contributing to a lasting anti-tumor effect. Unlike other cell therapies which require hospitalization and close monitoring, multiTAA-specific T cells are designed to be administered in an outpatient setting.

On June 12, 2023 Kura Oncology presented its corporate presentation (Presentation, Kura Oncology, JUN 12, 2023, View Source [SID1234632662]).

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On June 12, 2023 Innate Pharma SA (Euronext Paris: IPH; Nasdaq: IPHA) ("Innate" or the "Company") reported that interim efficacy results from the TELLOMAK Phase 2 study of lacutamab in advanced Mycosis Fungoides will be presented at the 17th International Conference on Malignant Lymphoma, being held in Lugano, June 13 – 17, 2023 (Press release, Innate Pharma, JUN 12, 2023, View Source [SID1234632659]). Efficacy results will be presented according to updated lymph node classification.

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Presentation details

Title: Lacutamab in patients with advanced mycosis fungoides (MF): efficacy results according to updated lymph node (LN) classification in the TELLOMAK study

Session: Focus on…T-Cell Lymphomas

Date and time: 15/06/2023, 17:50

Location: Room A

Speaker: Dr. Pierluigi Porcu, Director, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Sidney Kimmel Cancer Center, Jefferson Health Philadelphia, US

In addition, a Trial in Progress abstract of KILT, the Phase 2 study of lacutamab in peripheral T‑cell lymphoma led by The Lymphoma Study Association (LYSA) has been published in the 17‑ICML abstract book available online.

About Lacutamab

Lacutamab is a first-in-class anti-KIR3DL2 humanized cytotoxicity-inducing antibody that is currently in clinical trials for treatment of cutaneous T-cell lymphoma (CTCL), an orphan disease, and peripheral T cell lymphoma (PTCL). Rare cutaneous lymphomas of T lymphocytes have a poor prognosis with few efficacious and safe therapeutic options at advanced stages.

KIR3DL2 is an inhibitory receptor of the KIR family, expressed by approximately 65% of patients across all CTCL subtypes and expressed by up 90% of patients with certain aggressive CTCL subtypes, in particular, Sézary syndrome. It is expressed by up to 50% of patients with mycosis fungoides and peripheral T-cell lymphoma (PTCL). It has a restricted expression on normal tissues.

Lacutamab is granted European Medicines Agency (EMA) PRIME designation and US Food and Drug Administration (FDA) granted Fast Track designation for the treatment of patients with relapsed or refractory Sézary syndrome who have received at least two prior systemic therapies. Lacutamab is granted orphan drug status in the European Union and in the United States for the treatment of CTCL.

On June 12, 2023 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported new data and analyses from IMerge Phase 3 reporting robust durability of transfusion independence (TI), evidence for disease-modifying activity and favorable fatigue patient-reported outcomes (PRO) in lower risk myelodysplastic syndromes (MDS) patients treated with the Company’s first-in-class telomerase inhibitor, imetelstat, vs. placebo (Press release, Geron, JUN 12, 2023, View Source [SID1234632657]). The data and analyses were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting, which took place from June 8-11, 2023 in Frankfurt, Germany and virtually.

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"The new IMerge Phase 3 data and analyses presented at EHA (Free EHA Whitepaper) continue to support the unprecedented and differentiating attributes of imetelstat, including 24-week transfusion independence across key MDS subgroups, potential disease-modifying activity, as well as favorable patient-reported outcomes (PRO) data on meaningful improvement in fatigue," said Faye Feller, M.D., Executive Vice President, Chief Medical Officer of Geron. "Each of these qualities address important unmet needs for lower risk MDS patients due to the limitation of current treatment options. Submission of our New Drug Application later this month is a significant step to hopefully bring imetelstat to these transfusion burdened patients."

Presentation Title: Continuous Transfusion Independence with Imetelstat in Heavily Transfused Non-Del(5q) Lower Risk Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis Stimulating Agents in IMerge Phase 3

Top-line results from the primary analysis of IMerge Phase 3 presented earlier this month at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) (ASCO) (Free ASCO Whitepaper) Annual Meeting were also covered in the EHA (Free EHA Whitepaper) presentation, including the primary endpoint of 8-week transfusion independence (TI) and key secondary endpoint of 24-week TI were met with high statistical significance (P<0.001) for imetelstat-treated patients vs. placebo. Further, mean hemoglobin levels in imetelstat-treated patients increased significantly (P<0.001) over time compared to placebo patients.

In addition to these results, the EHA (Free EHA Whitepaper) presentation also provided new data and analyses highlighting clinically meaningful and durable TI for imetelstat-treated patients vs. placebo. As of a January 2023 data cut-off, 17.8% (21/118) of imetelstat-treated patients vs. 1.7% (1/60) of placebo-treated patients achieved 1-year TI (P=0.002), representing 63.6% of 24-week TI imetelstat responders.

Two new analyses presented at EHA (Free EHA Whitepaper) on TI responses by subgroups underscored the breadth of potential effect of imetelstat vs. placebo. The first analysis reported higher durability of TI for imetelstat-treated patients vs. placebo across key MDS subgroups:

Durability of RBC-TI for 8-Week TI Responders Across Key LR MDS Subgroups

Imetelstat
median, weeks (95% CI)

Placebo
median, weeks (95% CI)

Hazard ratio
(95% CI)

P-value

Overall

51.6 (26.9–83.9)

13.3 (8.0–24.9)

0.23 (0.09–0.57)

<0.001

WHO category

RS+

46.9 (25.9–83.9)

16.9 (8.0–24.9)

0.32 (0.11–0.95)

0.035

RS-

51.6 (11.9–NE)

11.2 (10.1–NE)

0.11 (0.01–1.43)

0.062

Prior RBC transfusion burden per IWG 2006

4–6 units/8 weeks

51.9 (24.9–122.9)

16.9 (10.1–24.9)

0.35 (0.13–0.96)

0.035

6 units/8 weeks

39.9 (15.9–NE)

8.4 (8.0–NE)

0.04 (0.003–0.48)

<0.001

IPSS risk category

Low

43.9 (25.0–NE)

15.1 (8.0–24.9)

0.26 (0.10–0.68)

0.004

Intermediate-1

51.6 (11.9–NE)

10.1 (NE–NE)

0.15 (0.01–2.47)

0.128

Baseline sEPO

≤500 mU/mL

51.6 (26.9–83.9)

13.3 (8.0–24.9)

0.21 (0.075–0.61)

0.002

>500 mU/mL

122.9 (8.14–NE)

14.6 (12.3–NE)

0.34 (0.03–3.85)

0.364

Prior ESA use

Yes

43.9 (26.9–80.0)

13.3 (8.0–24.9)

0.26 (0.10–0.72)

0.006

No

122.9 (8.14–NE)

14.6 (12.3–NE)

0.34 (0.03–3.85)

0.364

____________________
Data cut-off: October 13, 2022.

Hazard ratio (95% CI) from the Cox proportional hazard model, stratified by prior RBC transfusion burden (≥4 to ≤6 vs >6 RBC units/8 weeks during a 16-week period prior to randomization) and baseline IPSS risk category (low vs intermediate-1), with treatment as the only covariate. P-value (2-sided) for superiority of imetelstat vs placebo in hazard ratio based on stratified log-rank test.
ESA, erythropoiesis-stimulating agent; IPSS, International Prognostic Scoring System; IWG, International Working Group; LR-MDS, lower-risk myelodysplastic syndromes; NE, not estimable; RBC, red blood cell; RS, ring sideroblast; sEPO, serum erythropoietin; TI, transfusion independence.

The second analysis reported higher 24-week TI for imetelstat-treated patients vs. placebo across key MDS subgroups:

Comparable 24-Week RBC-TI Rate Across Key LR MDS Subgroups

Imetelstat
n/N (%)

Placebo,
n/N (%)

% Difference

(95% CI)

P-value

Overall

33/118 (28.0)

2/60 (3.3)

24.6 (12.64–34.18)

<0.001

WHO category

RS+

24/73 (32.9)

2/37 (5.4)

20.5 (−0.03–35.75)

0.003

RS-

9/44 (20.5)

0/23 (0.0)

0.11 (0.01–1.43)

0.019

Prior RBC transfusion burden per IWG 2006

4–6 units/8 weeks

19/62 (30.6)

2/33 (6.1)

24.6 (5.68–38.66)

0.006

6 units/8 weeks

39.9 (15.9–NE)

8.4 (8.0–NE)

0.04 (0.003–0.48)

<0.001

IPSS risk category

Low

23/80 (28.8)

2/39 (5.1)

23.6 (7.23–35.75)

0.003

Intermediate-1

10/38 (26.3)

0/21 (0)

26.3 (3.46–43.39)

0.009

Baseline sEPO

≤500 mU/mL

29/87 (33.3)

2/36 (5.6)

27.8 (10.46–39.71)

0.002

>500 mU/mL

4/26 (15.4)

0/22 (0)

15.4 (−5.81–35.73)

0.050

Prior ESA use

Yes

31/108 (28.7)

2/52 (3.8)

24.9 (11.61–35.00)

<0.001

No

2/10 (20)

0/8

20.0 (-23.47–55.78)

0.225

_____________
Data cut-off: October 13, 2022.

95% CI based on Wilson Score method. P-value determined by the Cochran-Mantel-Haenszel test, with stratification for prior RBC transfusion burden (≥4 to ≤6 vs >6 RBC units/8 weeks during a 16-week period prior to randomization) and baseline IPSS risk category (low vs intermediate-1) applied to randomization.

ESA, erythropoiesis-stimulating agent; IPSS, International Prognostic Scoring System; IWG, International Working Group; LR-MDS, lower-risk myelodysplastic syndromes; RBC, red blood cell; RS, ring sideroblast; sEPO, serum erythropoietin; TI, transfusion independence.

Additionally, the rate of 24-week TI was higher with imetelstat vs. placebo regardless of baseline mutation status, telomerase activity (TA), telomerase length (TL), and human telomerase reverse transcriptase (hTERT).

"For the first time at EHA (Free EHA Whitepaper), we see comparable 24-week TI across key MDS subgroups, which is especially meaningful for patients without ring sideroblasts (RS-) and very heavily transfusion burdened patients, who particularly have limited options today," said Uwe Platzbecker, M.D., Department of Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany, who presented the data at EHA (Free EHA Whitepaper) and is an IMerge investigator. "In addition to the durability of TI, imetelstat-treated patients also achieved significant increases in hemoglobin and reductions of transfusion units that could be life changing for lower risk MDS patients, who often present with symptomatic anemia and transfusion dependence."

As previously reported, the safety profile observed with imetelstat in IMerge Phase 3 was consistent with prior clinical experience with no new safety signals. The EHA (Free EHA Whitepaper) presentation provided new data on the consequences of the grade 3-4 thrombocytopenia and neutropenia which were most often reported during Cycles 1-3 and led to dose modifications. While approximately 50% of patients treated with imetelstat had dose reductions due to treatment emergent adverse events (TEAE), less than 15% of patients discontinued treatment due to TEAE. Discontinuation of imetelstat treatment in these patients due to a TEAE generally occurred late in treatment, with a median time to treatment discontinuation of 21.1 weeks (range 2.3 to 44.0 weeks).

Presentation Title: Disease-Modifying Activity of Imetelstat in Patients with Heavily Transfused Non-Del(5q) Lower Risk Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis Stimulating Agents in IMerge Phase 3

"In IMerge Phase 3, not only did we observe efficacy with imetelstat across the spectrum of genetic mutations associated with lower risk MDS, but we also saw a reduction in mutation burden, as measured by variant allele frequency (VAF). Furthermore, greater reduction of VAF in multiple genes correlated with the clinical endpoints of TI response, longer TI duration and increase in hemoglobin levels, suggesting the potential of imetelstat to modify the disease. This is the first therapy we know of that may alter the underlying biology of lower risk MDS by potentially reducing or eliminating malignant clones and improving ineffective erythropoiesis," said Valeria Santini, M.D., MDS Unit, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy, who presented the data at EHA (Free EHA Whitepaper) and is an IMerge investigator.

In the EHA (Free EHA Whitepaper) presentation, new data on cytogenetic responses and reductions in bone marrow RS supported the telomerase inhibition mechanism of action (MOA) of imetelstat. Among patients with cytogenetic abnormalities at baseline, the cytogenetic response rate was 35% (9/26) in imetelstat-treated patients and 15% (2/13) in the placebo group. Among cytogenetic responders, 89% (8/9) of patients in the imetelstat group and 50% (1/2) in the placebo group also achieved 8-week TI. A higher percentage of patients treated with imetelstat (40.8%) vs. placebo (9.7%) had a ≥50% reduction in central bone marrow RS. TI responses were enriched in patients achieving a ≥50% reduction in central bone marrow RS.

Furthermore, the EHA (Free EHA Whitepaper) presentation provided updated data on VAF reductions and new analyses on the correlation of such reductions with clinical responses which further support the potential disease-modifying activity of imetelstat. Reductions in variant allele frequency (VAF) of genes frequently mutated in MDS were greater for imetelstat-treated patients than placebo: SF3B1 (P< 0.001), TET2 (P= 0.032), DNMT3A (P= 0.019) and ASXL1 (P= 0.146). More patients treated with imetelstat vs. placebo had ≥50% VAF reduction in these mutations.

For patients with the SF3B1 mutation, 29.5% (23/78) of those treated with imetelstat vs. 2.6% (1/38) on placebo (P=0.001) had a ≥50% VAF reduction. Imetelstat treatment resulted in sustained reduction of SF3B1VAF over time. In the imetelstat group, 83% (19/23) of patients had 8-week TI among patients who achieved ≥50% maximum reduction from baseline inSF3B1 VAF vs. 38% (21/55) of those who did not.

Similarly, TI responders were also enriched in imetelstat-treated patients achieving ≥50% reduction in TET2 VAF. In the imetelstat group, 83% (10/12) of patients had 8-week RBC-TI among patients who achieved ≥50% maximum reduction from baseline in TET2 VAF vs 43% (10/23) of those who did not.

In imetelstat-treated patients, 24-week and 1-year TI responders were enriched in patients achieving ≥50% reduction in SF3B1andTET2VAF. VAF reduction in SF3B1, TET2and DNMT3Acorrelated with longer TI duration and increases in hemoglobin levels in imetelstat-treated patients. Further, 8-week and 24-week TI correlated with reduction in RS+ cells, cytogenetic responses and VAF reduction. These correlations suggest the disease-modifying activity of imetelstat.

Presentation Title: Analysis of Patient-Reported Fatigue in IMerge Phase 3 Trial of Imetelstat vs. Placebo in Heavily Transfused Non-Del(5q) Lower Risk Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis Stimulating Agents (ESA)

"The patient-reported outcome data from IMerge Phase 3 is particularly important as fatigue is a concern for lower risk MDS patients, most of whom are elderly. Furthermore, many of the current treatments for these patients cause fatigue. It is therefore very welcome news that imetelstat-treated patients showed sustained meaningful improvement in patient-reported fatigue vs. placebo. This is the first Phase 3 trial we know of to show an improvement in fatigue in lower risk MDS patients," stated Dr. Platzbecker.

The EHA (Free EHA Whitepaper) presentation described results from an exploratory analysis from IMerge Phase 3 of patient-reported fatigue conducted using Functional Assessment of Chronic Illness Therapy, or FACIT, a validated 13-item patient questionnaire. The analysis reported imetelstat-treated patients were more likely to have sustained meaningful improvement in fatigue, as well as experience such improvement more quickly.

Patients treated with imetelstat reported a lower rate of sustained meaningful deterioration in fatigue than placebo (43.2% vs 45.6%), while also receiving fewer transfusion units over time. For patients treated with imetelstat, there was a numerically higher percentage of patients reporting any episode of sustained meaningful improvement in fatigue. Further, patients receiving imetelstat experienced a shorter median time to first sustained clinically meaningful improvement in fatigue vs placebo (28.3 vs 65.0 weeks).

For patients treated with imetelstat, there were significant associations between sustained meaningful improvement in fatigue and 8- and 24-week TI and HI-E response rates, an association not seen in the placebo group.

Additional analysis showed that patients experiencing grade 3 or 4 neutropenia or thrombocytopenia had the same rates of sustained meaningful improvement in fatigue (52.5% and 53.4%, respectively) as the total imetelstat population (50%).

Additional Presentations at EHA (Free EHA Whitepaper)

In addition to these IMerge Phase 3 presentations, Geron collaborators presented a translational analysis from a subset of IMerge Phase 2 patients, as well as imetelstat myelofibrosis (MF) pre-clinical results.

The presentation slides and posters are available on the Publications section of Geron’s website: View Source

About IMerge Phase 3

The Phase 3 portion of the IMerge Phase 2/3 study is a double-blind, 2:1 randomized, placebo-controlled clinical trial to evaluate imetelstat in patients with IPSS Low or Intermediate-1 risk (lower risk) transfusion dependent MDS who were relapsed after, refractory to, or ineligible for, erythropoiesis stimulating agent (ESA) treatment, had not received prior treatment with either a HMA or lenalidomide and were non-del(5q). To be eligible for IMerge Phase 3, patients were required to be transfusion dependent, defined as requiring at least four units of packed red blood cells (RBCs), over an eight-week period during the 16 weeks prior to entry into the trial. The primary efficacy endpoint of IMerge Phase 3 is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, defined as the proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial (8-week TI). Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks (24-week TI), the duration of TI and the rate of hematologic improvement erythroid (HI-E), which is defined under 2006 IWG criteria as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least eight weeks or a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden. A total of 178 patients were enrolled in IMerge Phase 3 across North America, Europe, Middle East and Asia.

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from non-clinical studies and clinical trials of imetelstat provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the U.S. Food and Drug Administration for both the treatment of adult patients with transfusion dependent anemia due to Low or Intermediate-1 risk MDS that is not associated with del(5q) who are refractory or resistant to an erythropoiesis stimulating agent, and for adult patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus associated kinase (JAK) inhibitor treatment. Geron plans to submit a New Drug Application (NDA) in the U.S. in June 2023 and a Marketing Authorization Application (MAA) in the EU in the second half of 2023 in the lower risk MDS indication.