On November 14, 2022 Lumos Pharma, Inc. (NASDAQ:LUMO), a clinical-stage biopharmaceutical company focused on therapeutics for rare diseases, reported that interim results met expectations for its Phase 2 OraGrowtH210 Trial and Phase 2 Pharmacokinetic/Pharmacodynamic (PK/PD) OraGrowtH212 Trial evaluating oral LUM-201 for subjects with moderate (idiopathic) pediatric growth hormone deficiency (PGHD) who screened PEM-positive utilizing Lumos’s predictive enrichment marker (PEM) strategy (Press release, Lumos Pharma, NOV 14, 2022, View Source [SID1234623931]). Lumos also announced its financial results for the quarter ended September 30, 2022.

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"With the interim readout from our OraGrowtH210 and OraGrowtH212 trials announced today, we look forward to continuing to advance our clinical program and planning for our pivotal Phase 3 trial for potentially the first oral therapeutic for PGHD," said Rick Hawkins, Chairman and CEO of Lumos Pharma. "In the 1.6 mg/kg/day LUM-201 arm in the OraGrowtH210 study, we observed mean annualized height velocity of 8.6 cm/yr, in line with 8.3 cm/yr expected based on growth on rhGH for moderate PGHD subjects observed in multiple large datasets. We look forward to building on this initial data and expect to report primary outcome results from both OraGrowtH trials in the second half of 2023. Additionally, our collaboration with Mass General on an investigator sponsored trial evaluating LUM-201 in NAFLD continues, and the trial has dosed its first subject and continues to enroll."

Recent Highlights

Interim analyses for Phase 2 OraGrowtH210 and PK/PD OraGrowtH212 Trials met expectations. Interim analysis for Phase 2 OraGrowtH210 Trial demonstrated that the 1.6 mg/kg/day LUM-201 dose produced a mean annualized height velocity (AHV) of 8.6 cm/yr at six months on treatment for moderate (idiopathic) PGHD subjects. This met the expected AHV of 8.3 cm/yr observed for moderate naive-to-treatment PGHD subjects on rhGH at 12 months observed in Eli Lilly’s large Phase 4 GeNeSIS1 dataset and comparable findings from other large historical datasets.2,3 In addition, interim data from both OraGrowtH210 and OraGrowtH212 Trials demonstrated durability of LUM-201 response out to 12 months. The rhGH control arm produced an AHV of 11.05 cm at six months, an unexpected growth response in this moderate PGHD population. This higher than anticipated AHV in the rhGH arm was likely due both to the presence of a growth outlier and to imbalances in several baseline characteristics for this arm that are well documented in the published literature as predictors of greater growth response to rhGH. We believe LUM-201 will demonstrate a favorable safety profile as our interim data from both OraGrowtH trials show comparable safety and tolerability to the rhGH subjects in the trials. Interim data from both OraGrowtH trials support the selection of the 1.6 mg/kg/day LUM-201 dose for a pivotal Phase 3 trial. For a link to the Company’s conference call and presentation of the data refer to the Company’s website at Investor Relations – Events and Presentations.

Enrollment for the OraGrowtH210 Trial is now at ~80%. The primary outcome data on 80 subjects from OraGrowtH210 Trial and up to 24 subjects from our OraGrowtH212 Trial continues to be anticipated in the second half of 2023.

Enrollment Initiated in Massachusetts General Investigator-Initiated Trial evaluating LUM-201 in NAFLD. As previously announced, we entered into a clinical collaboration with Dr. Laura Dichtel and Massachusetts General Hospital to explore the potential of LUM-201 in Nonalcoholic Fatty Liver Disease (NAFLD) in an investigator sponsored pilot study. Enrollment in the trial has begun, and the first subject has been dosed. While we remain focused on our core LUM-201 program in PGHD, we are pleased to support Mass General’s exploration of LUM-201’s potential in this indication, a condition estimated to be prevalent in approximately 25% of adults worldwide. NAFLD can often advance to the more serious liver disease non-alcoholic steatohepatitis (NASH) with fibrosis, and NASH-associated liver failure is one of the leading causes of liver transplants in the United States.
1 Blum et al JES 2021, 2 Lechuga-Sancho et al JPEM 2009, 3 Ranke et al JCEM 2010,

Financial Results for the Quarter Ended September 30, 2022

Cash Position – Lumos Pharma ended the quarter on September 30, 2022 with cash and cash equivalents totaling $73.7 million compared to $94.8 million on December 31, 2021. The Company expects cash use of approximately $8.5 to $9.5 million in the fourth quarter of 2022. Cash on hand as of September 30, 2022 is expected to support operations into the second quarter of 2024, inclusive of the primary outcome data readout from OraGrowtH210 and OraGrowtH212 Trials anticipated in the second half of 2023.
R&D Expenses – Research and development expenses were $4.1 million for the quarter ended September 30, 2022, compared to $4.1 million for the same period in 2021, primarily due to an increase of $0.3 million in personnel-related expenses and $0.1 million in consulting expenses, offset by a decrease of $0.4 million in clinical trial and contract manufacturing expenses.
G&A Expenses – General and administrative expenses were $3.9 million for the quarter ended September 30, 2022, an increase compared to $3.4 million for the same period in 2021, primarily due to increases of $0.3 million in royalty expenses, $0.2 million in consulting expenses and $0.1 million in travel-related expenses, offset by a decrease of $0.1 million in other miscellaneous expenses.
Net Loss – The net loss for the quarter ended September 30, 2022 was $7.3 million compared to net loss of $7.5 million for the same period in 2021.
Lumos Pharma ended the third quarter 2022 with 8,375,271 shares outstanding.
About Lumos Pharma’s Clinical Trials

Phase 2 OraGrowtH210 Trial of Oral LUM-201 in PGHD

The OraGrowtH210 Trial is a multi-site, global trial evaluating orally administered LUM-201 at three dose levels (0.8, 1.6, 3.2 mg/kg/day) against a standard dose of injectable rhGH in approximately 80 subjects diagnosed with idiopathic (moderate) PGHD, which is less severe than organic PGHD. The objective of this trial is to identify the optimal dose of LUM-201 to be used in a Phase 3 registration trial, based on annualized height velocity from a 6-month dataset, and to prospectively confirm the preliminary validation of our Predictive Enrichment Marker (PEM) strategy. The interim analysis demonstrated that LUM-201 in the 1.6 mg/kg/day arm met expectations at six months of treatment with an AHV of 8.6 cm as compared to the AHV of 8.3 cm observed in the PEM-positive moderate naive-to-treatment PGHD subjects for 12 months on rhGH as derived from the large 20-year Phase 4 Eli Lilly GeNeSIS database. The complete set of six-month, primary outcome data for 80 subjects is anticipated in the second half of 2023. Subjects will be treated for up to 24 months.

OraGrowtH212 Trial Evaluating PK/PD and Pulsatility of Oral LUM-201 in PGHD

The OraGrowtH212 Trial is a single site, open-label trial evaluating the pharmacokinetic (PK) and pharmacodynamic (PD) effects of oral LUM-201 in up to 24 PGHD subjects at two dose levels, 1.6 and 3.2 mg/kg/day. The primary objective of the OraGrowtH212 Trial is to confirm prior clinical data demonstrating the amplified pulsatile release of endogenous growth hormone from LUM-201 therapy, contributes to its efficacy in PGHD. The primary endpoint for this trial is six months of PK/PD (pulsatility) and height velocity data in up to 24 subjects. Subjects will be allowed to remain on treatment until they reach their near-adult height. Primary data readout in up to 24 subjects is anticipated in the second half of 2023.

Switch Study, OraGrowtH213 Trial, Evaluating LUM-201 in OraGrowtH210 Subjects Previously on rhGH

The OraGrowtH213 Trial is an open-label, multi-center, Phase 2 study evaluating the growth effects and safety of LUM-201 following 12 months of daily rhGH in up to 20 idiopathic PGHD subjects who have completed the OraGrowtH210 Trial. Subjects will be administered LUM-201 at a dose level of 3.2 mg/kg/day for up to 12 months.

Lumos Pharma Collaboration with Massachusetts General Hospital Evaluating LUM-201 in NAFLD

Lumos Pharma has entered a collaboration with Massachusetts General Hospital (MGH) to evaluate LUM-201 in subjects with nonalcoholic fatty liver disease (NAFLD). GH is a critical stimulator of lipolysis, and shows anti-inflammatory effects, and preclinical data suggest that amplifying GH secretion has the potential to reduce hepatic steatosis and prevent NAFLD progression. Interestingly, enhancing the natural pulsatile release of GH has been shown clinically in short-term studies to be more efficacious in inducing lipolysis than continuous infusions of GH. This MGH investigator-initiated trial is a single-site, 6-month, open-label pilot study of daily oral LUM-201 in adults with NAFLD. The trial will evaluate a dose of 25 mg/day of LUM-201 in ten subjects with NAFLD and relative IGF-1 deficiency. The primary endpoints will be to determine the reduction in liver lipid content, inflammation, and fibrosis in these subjects administered LUM-201 compared to each subject’s baseline.

On November 14, 2022 RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, reported acceleration of opaganib’s development program for protection against radiation injury and cancer radiotherapy (Press release, RedHill Biopharma, NOV 14, 2022, View Source [SID1234623930]). A recent publication in the International Journal of Molecular Sciences, entitled "Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy", describes the collective results of eight U.S. government-funded in vivo studies by RedHill and Apogee Biotechnology Corporation ("Apogee"), as well as additional experiments, establishing opaganib’s1 potential nuclear radiation protection capabilities2.

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The publication highlights observations from numerous studies undertaken in both protection against radiation toxicity and cancer radiotherapy settings. In the relevant study models, opaganib was associated with protection of normal tissue, including gastrointestinal, from radiation damage due to ionizing radiation exposure or cancer radiotherapy, as well as improvement of antitumor activity, response to chemoradiation, and enhancement of tolerability and survival. Additional independent studies demonstrate the radioprotective capacity of opaganib in bone marrow, with opaganib showing enhanced survival in mice which were irradiated with both lethal and half-lethal whole-body radiation3.

"Subject to further alignment with FDA, we intend to follow the Animal Rule path to approval for opaganib, based on prior FDA guidance specific to opaganib for the intended indication. Development for medical countermeasures may follow the Animal Rule, with pivotal animal model studies of efficacy applicable when human clinical trials are not ethical or feasible. In addition, we intend to seek an expedited development timeframe and eligibility for a Medical Counter Measure Priority Review Voucher. Amid the growing awareness of the need for material threat medical countermeasures and the positive observations seen in these in vivo gastrointestinal focused radiation toxicity and cancer radiotherapy studies, along with external data indicating potential radioprotective capacity of opaganib in bone marrow, we have accelerated our development plans to further test opaganib as a protective agent against nuclear radiation toxicity. We have recently initiated a new study to assess protective effects of opaganib on radiation-induced hematologic and renal toxicity, with our partner Apogee. Another meeting with the FDA is scheduled to seek further guidance on the path to homeland security medical countermeasure approval. Discussions with multiple government agencies in the U.S. and internationally, regarding funding and other governmental support, have been initiated," said Gilead Raday, Chief Operating Officer and Head of R&D at RedHill. "Importantly, opaganib has demonstrated its safety and tolerability profile in more than 470 people in studies in other indications as well as expanded access use. As an oral, small molecule pill that is highly stable with a greater than five-year shelf-life, opaganib is easy to administer and distribute, supporting potential central countermeasures stockpiling by governments."
2

Mitigation of radiation toxicity is an area of governmental concern. A key priority for US government research efforts is focused on finding long shelf-life and easy to distribute and administer drugs for potential inclusion in the Strategic National Stockpile. Such drugs, to be used in mass casualty nuclear radiation incidents involving improvised nuclear or radiological dispersal devices, should have broad-acting protective capability, be able to be administered 24 hours or later after radiation exposure, be safe and be easy to distribute to large numbers of people needing treatment for the acute effects of high dose, whole-body radiation exposure.

Currently, to the best of the Company’s knowledge, only four FDA-approved medical countermeasure therapies are available. Three of these options are limited to effects caused by a small number of specific radioactive materials or to specific parts of the body. Potassium iodide (iodine pills) is intended to be used to protect against thyroid damage from the release of radioiodine. It works by preventing the thyroid from taking up radioactive iodine but seems to offer no protection to the rest of the body from irradiation and is of limited benefit unless given immediately upon exposure. The other two, Prussian Blue and DTPA (diethylenetriamine pentaacetate) provide protection by limiting the half-life in the body of specific materials: radioactive cesium and thallium, in the case of Prussian Blue, and radioactive plutonium, americium, and curium, in the case of DTPA. The fourth option, filgrastim, is intended for acute radiation syndrome resulting from high-dose radiation. Filgrastim does not seem to protect the body against the radiation itself and works by stimulating the creation of new white blood cells to protect the body from infections, which the body can no longer do in the presence of radiation-induced bone marrow destruction – as long as there are viable stem cells to stimulate.

We believe that opaganib’s protection would not be limited to specific radioactive materials or individual parts of the body. Much of the damage caused by radiation exposure is caused by inflammation secondary to the effects of ionizing radiation itself – known as Acute Radiation Syndrome. Opaganib, a sphingosine kinase-2 (SK2) inhibitor, is thought to exert its protective effects via an anti-inflammatory mechanism of action involving ceramide elevation and reduction of sphingosine 1-phosphate (S1P) in human cells – suppressing inflammatory damage to normal tissue and thus suppressing toxicity from unintended ionizing radiation exposure. It has also been reported in the literature that inhibition of sphingosine kinase 2 promotes the viability and robustness of hematopoietic stem cells, even in the face of radiation damage, supporting increased survival.

3
Protection against radiation toxicity studies with opaganib funded by U.S. government – summary of results:

Effect of opaganib on the lethality of TBI (Total Body Irradiation) in C57BL/6 mice
Vehicle-treated mice had pronounced symptoms indicative of severe GI damage, and all animals had to be euthanized within 14 days of radiation exposure. In contrast, protection was observed in the opaganib-treated group, in which 71% of the mice survived indefinitely.

Accumulation and pharmacodynamics of opaganib in mouse small intestine
In vehicle-treated mice, TNFα expression in the small intestines was observed to be up-regulated as early as 1 hour after Total Body Irradiation (TBI) and remained highly elevated for at least 26 hours. In contrast, pretreatment with opaganib was observed to not only block the induction of TNFα by TBI but also to reduce tissue TNFα levels below the baseline level indicating prolonged biodistribution of opaganib into the small intestine at sufficient levels to inhibit SK2 and suppress radiation-induced inflammation.

Effects of opaganib on GI damage following TBI
Post-radiation decreases in villus height (villi are a critical component of the intestines ability to absorb nutrients and indicative of intestinal health) were observed in the vehicle-treated animals compared with non-irradiated controls. In contrast, villus height was maintained in the opaganib-treated mice. Additionally, while there was evidence of cell depletion after 10 days in all groups, there were significantly more cells present at 4 days after irradiation in the opaganib-treated mice compared to vehicle controls (p<0.001) with this difference between treatments nearly resolving by Day 10.

Effect of opaganib on the lethality of partially shielded irradiation in C57BL/6 mice
In multiple scenarios, utilizing partial bone marrow shielding, involving different levels of irradiation and with different dosing regimens, opaganib was observed to reduce mortality, with the greatest improvement seen when opaganib was given both before and after irradiation, reducing mortality from 82% down to 4% (p<0.001) in the mice given the highest dose of radiation, 16 Gray (Gy).

Cancer radiotherapy studies with opaganib funded by U.S. government – summary of results:

In vitro effects of opaganib on cell radiosensitivity
Opaganib appeared to provide protection from IR-induced cell death, with observations showing the level of radiation need to kill 50% and 90% of intestinal epithelial cells increasing from 5.56 and 12.16 Gy respectively up to 6.46 and 13.2 Gy, respectively. Furthermore, opaganib was observed to increase the killing of transformed pancreatic cancer cells by radiation, particularly at the high dose of 15 Gy (p<0.05).

In vivo effects of combination of opaganib with radiation on tumor growth (multiple cancer-types):
Pancreatic cancer model: Treatment with either TBI alone or opaganib alone substantially reduced tumor growth (p<0.05 and p<0.001, respectively). Treatment with opaganib in combination with TBI was associated with significantly reduced tumor growth compared to the control group or to the TBI alone group (p<0.01 for each comparison) but was not significantly different from opaganib alone because of the strong antitumor activity of the drug in this model. Importantly, treatment with opaganib did not protect tumors from radiation treatment.

Melanoma and E0771 breast cancer model: Opaganib plus TBI was observed to have equal or better antitumor activity than TBI alone. Again, opaganib was not associated with a diminished tumor response to fractionated radiation treatment and increased weight loss from radiation treatment was not observed.

Head & neck cancer model: Treatment with opaganib alone was observed to slightly reduce tumor growth, while TBI + cisplatin was observed to substantially reduce tumor growth as compared to the control (vehicle) group (p<0.001). Treatment with opaganib in combination with TBI + cisplatin was associated with the greatest reduction in tumor growth and such treatment group had significantly better observations than TBI + cisplatin on Day 21 and after (p<0.02). Again, opaganib was not associated with diminished tumor response or increased weight loss.
4

About Opaganib (ABC294640)
Opaganib a new chemical entity, is an orally administered, first-in-class proprietary selective inhibitor of sphingosine kinase-2 (SK2) with suggested anti-inflammatory, anticancer, radioprotective and antiviral activity.

Opaganib is thought to work through the inhibition of multiple pathways, the induction of autophagy and apoptosis, and disruption of viral replication, through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SK2, DES1 and GCS).

In an oncology & radiological setting, opaganib has been observed to elevate ceramide and reduces sphingosine 1-phosphate (S1P) in cells, conditions that increase the antitumor efficacy of radiation while concomitantly suppressing inflammatory damage to normal tissue, leading to the potential to suppress toxicity from unintended ionizing radiation (IR) exposure and improve patient response to chemoradiation. Opaganib has received Orphan Drug designation from the U.S. FDA for the treatment of cholangiocarcinoma and is being evaluated in a Phase 2a study in advanced cholangiocarcinoma. Patient accrual, treatment and analysis in a prostate cancer study is ongoing. Opaganib has a Phase 1 chemoradiotherapy study protocol ready for IND submission.

Opaganib has demonstrated broad-acting, host-directed, antiviral activity against SARS-CoV-2, multiple variants, and several other viruses, such as Influenza A. Being host-targeted, and based on data accumulated to date, opaganib is expected to maintain effect against emerging viral variants. In prespecified analyses of Phase 2/3 clinical data in hospitalized patients with moderate to severe COVID-19, oral opaganib demonstrated improved viral RNA clearance, faster time to recovery and significant mortality reduction in key patient subpopulations versus placebo on top of standard of care. Data from the opaganib global Phase 2/3 study has been submitted for peer review and recently published in medRxiv.

Opaganib has also shown positive preclinical results in renal fibrosis, and has the potential to target multiple oncology, radioprotection, viral, inflammatory, and gastrointestinal indications.

On November 14, 2022 Protalix BioTherapeutics, Inc. (NYSE American:PLX) (TASE:PLX), a biopharmaceutical company focused on the development, production and commercialization of recombinant therapeutic proteins produced by its proprietary ProCellEx plant cell-based protein expression system, reported financial results for the third quarter ended September 30, 2022 and provided a business update on recent corporate and regulatory developments (Press release, Protalix, NOV 14, 2022, View Source [SID1234623929]).

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"We are happy we have reached a significant milestone for our company with the recent BLA resubmission to the FDA," said Dror Bashan, Protalix’s President and Chief Executive Officer. "We believe PRX-102, if approved, has the potential to significantly impact patients living with this rare, life-threatening genetic disease. As we approach potential approval and commercialization of PRX-102, we affirm our dedication to our mission of bringing new medicines to patients with serious diseases. We are grateful to our team members and external partners for their continued commitment to this program."

2022 Third Quarter and Recent Business Highlights

Regulatory Updates

●On November 9, 2022, the Company, together with its development and commercialization partner for PRX-102, Chiesi Farmaceutici S.p.A. ("Chiesi"), resubmitted a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA) for PRX-102 (pegunigalsidase alfa) for the treatment of adult patients with Fabry disease. The BLA re-submission included the final two year analyses of our phase III BALANCE clinical trial, which analyses were completed in July 2022, and long-term data from our open-label extension study of PRX-102 in adult patients treated with a 2 mg/kg every four weeks dosage of PRX 102. The initial BLA included a comprehensive set of preclinical, clinical and manufacturing data compiled from our completed phase I/II clinical trial of PRX 102, including the related extension study, interim clinical data from our phase III BRIDGE clinical trial and safety data from our on-going clinical studies of PRX 102 in adult patients receiving 1 mg/kg every two weeks.
Third Quarter 2022 Financial Highlights

●The Company recorded revenues from selling goods of $8.8 million during the three months ended September 30, 2022, an increase of $4.3 million, or 96%, compared to revenues of $4.5 million for the three months ended September 30, 2021. An increase of $3.4 million in sales to Pfizer Inc., resulting from timing differences, and an increase of $2.4 million in sales to Chiesi was partially offset by a decrease of $1.5 million in sales to Brazil resulting from timing differences.
●Revenue from licenses and R&D services for the three months ended September 30, 2022 were $5.4 million, a decrease of $2.1 million, or 28%, compared to revenues of $7.5 million for the three months ended September 30, 2021. Revenues from license and R&D services are comprised primarily of revenues we recognized in connection with the Chiesi Agreements.
●Cost of goods sold was $7.1 million for the three months ended September 30, 2022, an increase of $3.4 million, or 91%, from cost of goods sold of $3.7 million for the three months ended September 30, 2021. The increase in cost of goods sold was primarily the result of the increase in sales of goods.
●For the three months ended September 30, 2022, our total research and development expenses were approximately $7.4 million comprised of approximately $4.9 million in subcontractor-related expenses, approximately $1.7 million of salary and related expenses, approximately $0.2 million of materials-related expenses and approximately $0.6 million of other expenses. For the three months ended September 30, 2021, our total research and development expenses were approximately $7.3 million comprised of approximately $4.8 million in subcontractor-related expenses, approximately $1.6 million of salary and related expenses, approximately $0.1 million of materials-related expenses and approximately $0.8 million of other expenses. Total increase in research and developments expenses was $0.1 million, or 1%, for the three months ended September 30, 2022 compared to the three months ended September 30, 2021.
●Selling, general and administrative expenses were $2.8 million for the three months ended September 30, 2022, a decrease of $0.2 million, or 7%, compared to $3.0 million for the three months ended September 30, 2021. The decrease was primarily due to a decrease in salary related and selling costs.
●Financial expenses, net were $0.4 million for the three months ended September 30, 2022, compared to $2.3 million for the three months ended September 30, 2021. The decrease resulted primarily from lower interest and debt amortization costs due to a decrease in our outstanding notes from an aggregate principal amount of $57.92 million of 2021 Notes to an aggregate principal amount of $28.75 million of 2024 Notes, and an increase in the exchange rate of New Israeli Shekels for U.S. Dollars over the period.
●Cash, cash equivalents and short-term bank deposits were approximately $20.8 million at September 30, 2022.
●Net loss for the three months ended September 30, 2022 was approximately $3.6 million, or $0.07 per share, basic and diluted, compared to a net loss of approximately $4.2 million, or $0.09 per share, basic and diluted, for the same period in 2021.
Conference Call and Webcast Information

The Company will host a conference call today, November 14, 2022, at 8:30 a.m. Eastern Standard Time, to review the corporate and regulatory developments, which will also be available by webcast. To participate in the conference call, please dial the following numbers prior to the start of the call:

Please access the websites at least 15 minutes ahead of the conference to register, download and install any necessary audio software.

The conference call will be available for replay for two weeks on the Events Calendar of the Investors section of the Company’s website, at the above link.

On November 14, 2022 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported financial results for the third quarter ended September 30, 2022 (Press release, Cogent Biosciences, NOV 14, 2022, View Source [SID1234623928]).

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"We are excited to announce the initiation of our Phase 3 PEAK trial in imatinib-resistant, second line GIST patients and look forward to presenting an update from our Phase 2 APEX trial in ASM patients in an oral presentation at ASH (Free ASH Whitepaper) 2022," said Andrew Robbins, President and CEO of Cogent Biosciences. "Our team has made tremendous progress this year, advancing our three bezuclastinib clinical trials, PEAK, APEX, and SUMMIT, recently presenting new data on our novel FGFR2 and ErbB2 selective programs, and delivering an optimized formulation of bezuclastinib which will significantly improve the patient experience."

Recent Business Highlights

Initiated the randomized portion of PEAK, a global Phase 3 clinical trial in GIST patients who have progressed following imatinib therapy. The trial is designed to explore the efficacy of bezuclastinib in combination with sunitinib compared to sunitinib alone.
The experimental arm of the PEAK trial includes a 600 mg daily dose of an optimized formulation of bezuclastinib, supplied as 75 mg tablets, which in the lead-in portion of the study demonstrated clinical exposures equivalent to the 1,000 mg daily dose of the original formulation used in the GIST Phase 1/2 clinical trial.

Presented preclinical data at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) annual meeting on a next-generation fibroblast growth factor receptor 2 (FGFR2) program, which retains potency across all primary, gatekeeper and molecular brake resistance mutations, including N549K and V564I, while sparing FGFR1 inhibition. This program remains on track for IND in 2023, with IND-enabling activities to commence early next year.

Presented preclinical data at ENA on a novel ErbB2 mutant selective program which demonstrates robust cellular inhibition of all key resistance and primary driver mutations, including L755S, V842I and S310F/Y, while sparing wild type EGFR target engagement.
Upcoming Milestones

Present updated clinical data from APEX, a global, multicenter Phase 2 clinical trial of bezuclastinib in patients with advanced systemic mastocytosis (AdvSM) in an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on Sunday, December 11, 2022. The presentation will include measures of clinical activity, including initial patient response assessment, in addition to pharmacokinetic and safety data. Cogent will host an investor webcast on December 12, 2022 at 8:00 am ET to discuss these data.
Preliminary Safety and Efficacy from Apex, a Phase 2 Study of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Adults with Advanced Systemic Mastocytosis (AdvSM)
Presenter: Daniel DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute
Present initial safety and pharmacokinetic data from the PEAK lead-in study at the Connective Tissue Oncology Society (CTOS) annual meeting, November 16-19, 2022.
Peak Study: A Phase 3 Randomized, Open-label, Multicenter Clinical Study of Bezuclastinib (CGT9486) and Sunitinib Versus Sunitinib in Patients with Gastrointestinal Stromal Tumors
Presenter: Andrew J. Wagner, MD, Ph.D., Associate Chief Medical Officer at the Dana Farber Cancer Institute
Present initial clinical efficacy results from refractory GIST patients receiving bezuclastinib plus sunitinib in the PEAK lead-in study during first half of 2023.

Present initial clinical data from SUMMIT, a randomized, double-blind, placebo-controlled, global, multicenter, Phase 2 clinical trial of bezuclastinib in patients with nonadvanced systemic mastocytosis (NonAdvSM), now in the second half of 2023. Based on the exciting performance of bezuclastinib’s optimized formulation in the PEAK lead-in trial, as well as in a separate healthy volunteer study, the SUMMIT trial protocol will be amended to allow for the optimized formulation to be introduced during the dose exploration phase.
Begin IND enabling studies for a potentially best-in-class, FGFR1-sparing, pan-FGFR2 mutation tyrosine kinase inhibitor in early 2023. This program is Cogent’s first internally developed research program and has been designed to overcome the clinical challenges of emergent FGFR2 treatment resistance, including the gatekeeper and molecular brake mutations that are the most common drivers of resistance, as well as off-target FGFR1 related adverse events that may limit the use of currently available and development stage FGFR2 tyrosine kinase inhibitors.
Third Quarter 2022 Financial Results

Cash Position: As of September 30, 2022, cash, cash equivalents and marketable securities were $289.1 million, as compared to $325.6 million as of June 30, 2022. The company believes that its cash, cash equivalents and marketable securities will be sufficient to fund its operating expenses and capital expenditure requirements into 2025. During the third quarter of 2022 Cogent incurred one-time cash payments of $8.6 million mainly related to the build-out and equipment costs associated with its newly-constructed Research Lab in Boulder, CO.

R&D Expenses: Research and development expenses were $29.9 million for the third quarter of 2022 as compared to $14.8 million for the third quarter of 2021. R&D expenses include non-cash stock compensation expense of $2.1 million for the third quarter of 2022 compared to $1.4 million for the third quarter of 2021. Additional increases resulted from costs associated with the APEX, SUMMIT and PEAK clinical trials as well as costs related to expanding the Cogent Research Team, which was formed in the second quarter of 2021.

G&A Expenses: General and administrative expenses were $6.9 million for the third quarter of 2022 as compared to $5.0 million for the third quarter of 2021. G&A expenses include non-cash stock compensation expense of $2.6 million for the third quarter of 2022 compared to $2.0 million for the third quarter of 2021.

Net Loss: Net loss was $35.1 million for the third quarter of 2022 as compared to a net loss of $19.1 million for the same period of 2021.

On November 14, 2022 AstraZeneca and Daiichi Sankyo reported that it’s Enhertu (trastuzumab deruxtecan) has been recommended for approval in the European Union (EU) as monotherapy for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen (Press release, AstraZeneca, NOV 14, 2022, View Source [SID1234623927]).

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on results from the DESTINY-Gastric02 and the DESTINY-Gastric01 Phase II trials.

In DESTINY-Gastric02, conducted in patients from North America and Europe, updated results showed treatment with Enhertu resulted in a confirmed objective response rate (ORR) of 41.8% as assessed by independent central review (ICR). Median duration of response (DoR) was 8.1 months and median overall survival (OS) was 12.1 months. Primary results from the DESTINY-Gastric02 Phase II trial were presented at the 2021 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, with the updated data presented at ESMO (Free ESMO Whitepaper) 2022.1

In DESTINY-Gastric01, conducted in patients from Japan and South Korea, updated results showed treatment with Enhertu resulted in an ORR of 51.3% versus 14.3% with chemotherapy (irinotecan or paclitaxel). Patients treated with Enhertu had a 40% reduction in the risk of death versus patients treated with chemotherapy (based on a hazard ratio of 0.60; 95% confidence interval: 0.42-0.86, p=0.01) with a median OS of 12.5 months versus 8.9 months. Additionally, confirmed ORR, a major efficacy outcome, was 42.0% with Enhertu versus 12.5% with chemotherapy as assessed by ICR. The primary analysis was published in The New England Journal of Medicine,2 with the updated data presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Gastric cancer is usually diagnosed in the advanced stage in many European countries and patients face high mortality rates. If approved, Enhertu would be the first HER2-directed medicine for patients with advanced gastric cancer in the European Union in more than a decade."

Ken Takeshita, Global Head, Oncology R&D, Daiichi Sankyo, Inc, said: "Enhertu is the first HER2-directed medicine to demonstrate a significant improvement in overall survival compared to chemotherapy in patients with gastric cancer following initial treatment with a HER2-directed medicine in the advanced or metastatic setting. The CHMP opinion recognises the high unmet need in this patient population and brings us one step closer to bringing this medicine to patients with gastric cancer in Europe."

In both trials, the safety profiles observed in patients treated with Enhertu were consistent with those seen in other trials of Enhertu with no new safety signals identified.

Enhertu is approved in the US and several other countries for locally advanced or metastatic HER2-positive gastric cancer.

Notes

HER2-positive gastric cancer
Gastric (stomach) cancer is the fifth most common cancer worldwide and the fourth highest leading cause of cancer mortality, with a five-year global survival rate of 5% to 10% for advanced or metastatic disease.3-5 Approximately one million new patients were diagnosed with gastric cancer in 2020, with 768,000 deaths reported globally.6 In Europe, approximately 136,000 cases of gastric cancer are diagnosed annually, and Eastern Europe has the second highest incidence of gastric cancer worldwide after Eastern Asia.5-6 Gastric cancer is the sixth leading cause of cancer death in Europe and is typically diagnosed in the advanced stage. Even when diagnosed in earlier stages of the disease, the survival rate remains modest.5-7

Approximately one in five gastric cancers are HER2-positive.8,9 HER2 is a tyrosine kinase receptor growth promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers.8 HER2 overexpression may be associated with a specific HER2 gene alteration known as HER2 amplification.9

Recommended first-line treatment for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy.10 For patients with metastatic gastric cancer that progresses following initial treatment with a trastuzumab-based regimen, treatment options are limited, and in many regions in the world there are no additional HER2 directed medicines available.2,11,12

DESTINY-Gastric02
DESTINY-Gastric02 is an open-label, single-arm Phase II trial in Western patients evaluating the efficacy and safety of Enhertu (6.4mg/kg) in patients with HER2-positive metastatic and/or unresectable gastric or GEJ adenocarcinoma with disease progression on or after a trastuzumab-containing regimen.

The primary endpoint of DESTINY-Gastric02 is confirmed ORR based on ICR. Secondary endpoints include progression-free survival (PFS), OS, DoR and safety.

DESTINY-Gastric02 enrolled 79 patients at multiple sites in North America and Europe. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Gastric01
DESTINY-Gastric01 is a randomised, open-label Phase II trial evaluating the efficacy and safety of Enhertu (6.4mg/kg) in patients from Japan and South Korea with primarily HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+/in-situ hybridisation [ISH]+) advanced gastric cancer or GEJ adenocarcinoma whose tumours have progressed on two or more prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy and trastuzumab. Patients were randomised 2:1 to receive Enhertu or physician’s choice of chemotherapy (paclitaxel or irinotecan monotherapy).

The primary endpoint of DESTINY-Gastric01 is ORR. Secondary endpoints include OS, PFS, DoR, disease control rate and time to treatment failure, as well as pharmacokinetic and safety endpoints.

DESTINY-Gastric01 enrolled 187 patients at multiple sites in Japan and South Korea. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/kg) is approved in more than 35 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in several countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

Enhertu (5.4mg/kg) is approved in Brazil and the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy, based on the results of the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

Enhertu development programme
A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for Enhertu in breast and gastric cancer are currently under review in several other countries based on the DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01 and DESTINY-Gastric02 trials, respectively.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in gastrointestinal cancers
AstraZeneca has a broad development programme for the treatment of gastrointestinal (GI) cancers across several medicines and a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new cancer cases leading to approximately 3.6 million deaths.13

Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic and colorectal cancers.

Enhertu, a HER2-directed antibody drug conjugate, is approved in the US and several other countries for HER2-positive advanced gastric cancer and is being assessed in colorectal cancer. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Imfinzi (durvalumab) is approved in the US and several other countries in combination with chemotherapy (gemcitabine plus cisplatin) for advanced biliary tract cancer and in the US in combination with Imjudo (tremelimumab) in unresectable hepatocellular carcinoma. Imfinzi is being assessed in combinations, including with Imjudo, in liver, oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

Lynparza (olaparib), a first-in-class PARP inhibitor, is approved in the US and several other countries for the treatment of BRCA-mutated metastatic pancreatic cancer. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

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