GLP-1R

Pictured: Illustration of a liver with signs of fibrosis/iStock, Mohammed Haneefa Nizamudeen The approval of Madrigal Pharmaceuticals’ Rezdiffra (resmetirom) for metabolic dysfunction-associated steatohepatitis is expected to open doors for future therapies, while also setting the efficacy and safety bar for upcoming candidates, according to a Friday report from data analytics firm GlobalData. Madrigal’s regulatory victory will help it “reap the benefits of the first-to-market therapy,” Sravani Meka, GlobalData senior pharma analyst, said in a statement. Rezdiffra will be able to enjoy market dominance while its competitors are still trialing their candidates, and the therapy will be able to establish itself in clinical guidelines and standards. This advantage will help Madrigal carve out its own piece of the MASH market, which GlobalData estimates to reach nearly $26 billion in 2032 across the seven major markets—the U.S., France, Germany, Italy, Spain, the U.K. and Japan. Rezdiffra will also “set the standard for all other treatments in development” and “future therapies will now have to meet or outperform the efficacy and safety data from resmetirom’s Phase III MAESTRO studies,” Meka said. The FDA granted accelerated approval to Rezdiffra on Thursday, making it the first-ever authorized therapy for metabolic dysfunction-associated steatohepatitis (MASH). Rezdiffra can now be used alongside diet and exercise to treat patients with moderate to advanced liver fibrosis. The treatment’s continued approval may depend on a future confirmatory trial validating its clinical benefit. Importantly, the FDA’s clearance does not require patients to have undergone liver biopsies to be treated with Rezdiffra. In an investor note on Friday, William Blair analysts Andy Hsieh and Alexandra Ramsey said that this could “buoy biotech stocks” and “potentially accelerate and broaden patient access.” Rezdiffra’s active ingredient is resmetirom, which is a small molecule, liver-directed drug that works by activating the thyroid hormone receptor beta (THR-β), which is highly enriched in the liver. The agonism of THR-β helps reduce intrahepatic triglyceride levels and boost lipid metabolism. According to Madrigal’s website, THR-β signaling is impaired in MASH patients, which triggers mitochondrial dysfunction, lipotoxicity and fibrosis. The FDA’s approval was supported by data from a comprehensive clinical development program that includes 18 clinical trials, four of which are late stage. The core of Madrigal’s program is MAESTRO-NASH, which hit both of its primary endpoints with both 80-mg and 100-mg doses of Rezdiffra eliciting significantly higher rates of MASH resolution and improvement in liver fibrosis compared to placebo. By clearing the FDA’s regulatory hurdles, Rezdiffra has bested at least 20 other MASH programs that have been suspended or discontinued, including Intercept’s obeticholic acid tablets and Akero’s efruxifermin. Still, other biotechs are on Madrigal’s heels developing their own MASH therapies with differentiated mechanisms of action. Among the potential competitors are Novo Nordisk and Eli Lilly, which are developing their respective top-selling GLP-1 receptor agonists semaglutide and tirzepatide for MASH. Also hoping to target the lucrative market is 89bio, whose FGF21 analog pegozafermin met its Phase IIb primary histology endpoint in March 2023. For the William Blair analysts, Viking’s candidate VK2809 holds the most promise. Currently being assessed in the Phase IIb VOYAGE study, VK2809 could “potentially outshine Rezdiffra’s clinical profile,” Hiseh and Ramsey contend. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

A chronic metabolic disease in which fat buildup leads to worsening liver function that can ultimately require an organ transplant now has its first FDA-approved therapy, a once-daily pill developed by Madrigal Pharmaceuticals. The FDA decision Thursday is for adults with noncirrhotic non-alcoholic steatohepatitis, or NASH. The approval specifically covers those who have reached the point of moderate-to-advanced liver scarring, which is also called fibrosis. The Conshohocken, Pennsylvania-based company’s drug, known in development as resmetirom, will be marketed under the brand name Rezdiffra. “We’ve had patients waiting and waiting for something that could impact underlying fibrosis in the setting of NASH, and this truly represents a milestone achievement that frankly I, and many others, have been working on since the turn of the century,” Steven Harrison, medical director of Pinnacle Clinical Research and the lead investigator for Rezdiffra’s pivotal clinical trial, said during a Madrigal conference call Thursday evening. NASH is sometimes called a “silent disease” because it rarely presents with any symptoms. But the disorder, which much of the liver field is starting to call metabolic dysfunction-associated steatohepatitis, or MASH, develops over time as the fatty buildup leads to inflammation and fibrosis. Fibrosis is classified according to four stages with stage 4 being liver cirrhosis. Because MASH has no symptoms, its exact prevalence is not known. But the FDA cites an estimate of about 6 to 8 million people in the U.S. who have this disease with moderate to advanced liver scarring. In this range, patients have stage 2 or stage 3 fibrosis. Rezdiffra is a small molecule designed to target and activate a receptor in the liver called thyroid hormone receptor beta (THR-beta). This receptor mediates metabolic activity in the organ, including the lowering of fat levels. The Madrigal molecule selectively activates THR-beta without also activating THR-alpha and sparking safety problems associated with hitting that receptor. Resmetirom was discovered in the labs of Roche; Madrigal licensed global rights to the molecule in 2011 and commenced clinical development. The Phase 3 study’s two main goals were to measure resolution of MASH and to show an improvement in fibrosis by at least one stage with no worsening in score according to a scale used to measure the severity of the liver disorder. In the trial, biopsy-confirmed results showed MASH resolution with no worsening of fibrosis was achieved by 25.9% of those given a low dose of the Madrigal drug and 29.9% of those treated with the high dose. In the placebo arm, 9.7% of patients achieved this goal. Fibrosis improvement by at least one stage was achieved by 24.2% of patients in the low-dose group and 25.9% of patients given the high dose. Just 14.2% of patients who received a placebo met this goal. The side effects reported for Rezdiffra include diarrhea and nausea. Results were published last month in the New England Journal of Medicine. The FDA approval covers three doses of Rezdiffra, which is dosed according to patient weight and is intended to be used alongside diet and exercise. Though the clinical trial enrolled patients whose disease was confirmed by liver biopsy, a biopsy is not a requirement in the drug’s label. Patients will be diagnosed with non-invasive tests, Madrigal CEO Bill Sibold said. In an interview ahead of the Rezdiffra approval announcement, Dr. Lisa Ganjhu, a gastroenterologist and hepatologist at NYU Langone Health, said MASH can be diagnosed as part of routine metabolic tests that are part of a patient’s annual exam. When the tests flag a potential problem with liver or kidney function, the next step could be an ultrasound that spots the fat buildup on the liver. Ganjhu, who was not involved in Rezdiffra’s clinical trials, said not all fatty liver disease turns into fibrosis. But she added that the Madrigal drug is promising for patients because it is the first medication to show it can reverse that scarring. “We really have nothing but diet and exercise for patients right now,” Ganjhu said. “This is something that could get them better from stage 3 [fibrosis] to 2, or stage 2 to 1. Any reduction in fibrosis reduces the risk of developing cirrhosis or other complications down the road.” Leerink Partners analyst Thomas Smith wrote in an investor note that Rezdiffra’s label represents a near best-care scenario for Madrigal. In addition to no liver biopsy requirement, there are no unexpected safety concerns or restrictive warnings. Smith said it remains to be seen whether payers will impose biopsy or monitoring requirements. But he added that Rezdiffra’s approval as the first NASH/MASH therapy reduces risk for entire field, which has seen a long list of companies encounter clinical trial failures and regulatory setbacks. “We consider the approval of the first therapeutic specifically for NASH to significantly derisk the regulatory pathway and establish a precedent for other companies developing therapeutic candidates for the indication,” Smith said. “Moreover, we expect the necessary launch activities of increasing patient awareness, educating physicians, and developing payor agreements that are key to establishing a new commercial market will lay a positive foundation for follow-on companies.” Companies still in the field of NASH/MASH drug development include Viking Therapeutics, whose THR-beta-targeting small molecule is in Phase 2b testing. Those with different approaches to the metabolic disorder include 89bio, Akero Therapeutics, and Sagimet Biosciences. Diabetes and obesity drugs that target the GLP-1 receptor are also showing the potential to treat MASH. Recently, Boehringer Ingelheim and Eli Lilly posted encouraging mid-stage data for their respective drugs. NYU Langone’s Ganjhu acknowledged the potential of GLP-1 drugs to treat MASH. But she said that those drugs work by reducing fat overall, while Rezdiffra specifically reduces fat in the liver. Madrigal set an annual wholesale price of $47,400 for Rezdiffra. That’s within the $39,600 to $50,100 price range that drug price group ICER said would be cost-effective. Sibold said Rezdiffra is a high-value medicine addressing a disease that poses a high burden to patients and the healthcare system. In setting the drug’s price, Madrigal aimed to balance value and patient access. The company expects to launch the drug in April, distributing it through a limited specialty pharmacy network. The FDA decision for Rezdiffra is an accelerated approval that requires Madrigal to produce additional data from confirmatory studies. An ongoing outcomes study will serve as that confirmatory study to potentially support full FDA approval of the drug.

Interim data from initial dose escalation cohorts from Phase 1 trial of TERN-701 (allosteric BCR-ABL) for treatment of CML expected in second half of 2024 Top-line data from Phase 1 trial of TERN-601 (oral GLP-1) for obesity expected in second half of 2024 Cash, cash equivalents and marketable securities of $263 million, expected to provide runway into 2026 FOSTER CITY, Calif., March 14, 2024 (GLOBE NEWSWIRE) -- Terns Pharmaceuticals, Inc. (“Terns” or the “Company”) (Nasdaq: TERN), a clinical-stage biopharmaceutical company developing a portfolio of small-molecule product candidates to address serious diseases, including oncology and obesity, today reported financial results for the fourth quarter and full year ended December 31, 2023 and provided corporate updates. “I joined Terns last month at a pivotal stage in the company’s growth as we advance towards initial data readouts from our Phase 1 clinical programs for TERN-601, our oral small molecule GLP-1 agonist for obesity, and TERN-701, our allosteric BCR-ABL inhibitor for CML. Importantly, our global Phase 1 trial of TERN-701 allows for the enrollment of second line CML patients, which makes the study attractive for participants given that there is no allosteric inhibitor currently approved for 2L CML patients,” said Amy Burroughs, chief executive officer of Terns. “Terns made meaningful progress throughout 2023, as highlighted by the initiation of these two clinical programs, the positive Phase 2 data readout from our potentially best in class THR-β and the advances in discovery for our small-molecule GIPR modulators for obesity.” Recent Pipeline Developments and Anticipated Milestones TERN-701: Oral, allosteric BCR-ABL tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML) Global Phase 1 CARDINAL trial initiated in fourth quarter 2023 and is progressing CARDINAL is a global, multicenter, open-label, two-part Phase 1 clinical trial to evaluate the safety, pharmacokinetics (PK) and efficacy of TERN-701 in patients with previously treated CMLThe study design leverages insights from the ongoing Phase 1 trial in China, which support a starting dose that appears safe and clinically active based on emerging early clinical data The CARDINAL trial design provides multiple opportunities to potentially differentiate TERN-701 in the CML treatment landscape Opportunity to efficiently develop TERN-701 as a dose-optimized allosteric inhibitor for CMLInclusion of second-line (2L) chronic phase CML patients, which better positions Terns to potentially move directly into a 2L (or earlier line) pivotal studyReduced competition for trial enrollment as no allosteric inhibitor is currently approved for 2L CML patients Interim data from initial CARDINAL dose escalation cohorts expected in the second half of 2024In March 2024, the United States Food and Drug Administration (FDA) granted Orphan Drug Designation for TERN-701 for the treatment of chronic myeloid leukemiaTerns plans to host a virtual KOL event in mid-2024 to focus on the interpretation of early CML datasets TERN-601: Oral, small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist for obesity Phase 1 clinical trial of Terns’ lead oral GLP-1 receptor agonist in healthy obese or overweight participants is ongoing Primary endpoints include safety and tolerability assessmentsSecondary and exploratory endpoints include PK and change in body weight over 28 days Top-line data, including 28-day body weight loss, expected in the second half of 2024Terns continues preclinical efforts to identify promising oral, small-molecule combination candidates for obesity (e.g., GLP-1 + THR-β, GLP-1 + GIPR agonist / antagonist) TERN-501: Oral, thyroid hormone receptor-beta (THR-β) agonist Terns continues to evaluate opportunities for TERN-501 in metabolic diseases Based on non-clinical studies, THR-β is an orthogonal mechanism to GLP-1, potentially providing broader metabolic and liver benefits in addition to increased weight lossNon-clinical data suggests that TERN-501 may augment the weight loss effects of a GLP-1 receptor agonist, as demonstrated in a diet-induced obese mouse model Terns has decided to limit spend in MASH given the current regulatory and clinical development requirements for the indication TERN-800 Series: Oral, small-molecule glucose-dependent insulinotropic polypeptide receptor (GIPR) modulators Discovery efforts are ongoing for the TERN-800 series of small molecule GIPR modulators for obesityGIPR modulators (agonists and antagonists) have the potential for combination with GLP-1 receptor agonists, such as TERN-601 Corporate Updates In February 2024, Terns announced the appointment of Amy Burroughs as chief executive officer and board member of Terns Fourth Quarter and Full Year 2023 Financial Results Cash Position: As of December 31, 2023, cash, cash equivalents and marketable securities were $263.4 million, as compared with $283.1 million as of December 31, 2022. Based on its current operating plan, Terns expects these funds will be sufficient to support its planned operating expenses into 2026. Research and Development (R&D) Expenses: R&D expenses were $17.5 million and $63.5 million for the quarter and year ended December 31, 2023, respectively, as compared with $10.7 million and $39.6 million for the quarter and year ended December 31, 2022, respectively. General and Administrative (G&A) Expenses: G&A expenses were $6.6 million and $39.1 million for the quarter and year ended December 31, 2023, respectively, as compared with $6.2 million and $22.4 million for the quarter and year ended December 31, 2022, respectively. Net Loss: Net loss was $21.0 million and $90.2 million for the quarter and year ended December 31, 2023, respectively, as compared with $15.8 million and $60.3 million for the quarter and year ended December 31, 2022, respectively. Financial Tables Terns Pharmaceuticals, Inc. Consolidated Statements of Operations (Unaudited; in thousands except share and per share amounts) Quarter Ended December 31, Year Ended December 31, 2023 2022 2023 2022 Operating expenses: Research and development $17,459 $10,658 $63,497 $39,617 General and administrative 6,599 6,170 39,061 22,412 Total operating expenses 24,058 16,828 102,558 62,029 Loss from operations (24,058) (16,828) (102,558) (62,029)Interest income 3,333 1,328 12,901 2,110 Other expense, net (245) (4) (314) (68)Loss before income taxes (20,970) (15,504) (89,971) (59,987)Income tax expense (49) (318) (239) (358)Net loss $(21,019) $(15,822) $(90,210) $(60,345) Net loss per share, basic and diluted $(0.29) $(0.29) $(1.27) $(1.67)Weighted average common stock outstanding, basic and diluted 72,333,196 54,696,352 71,259,239 36,033,045 Terns Pharmaceuticals, Inc. Selected Balance Sheet Data (Unaudited; in thousands) December 31, 2023 2022Cash, cash equivalents and marketable securities $263,440 $283,114Total assets 268,517 287,026Total liabilities 13,150 10,083Total stockholders’ equity 255,367 276,943 About Terns PharmaceuticalsTerns Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing a portfolio of small-molecule product candidates to address serious diseases, including oncology and obesity. Terns’ pipeline includes three clinical stage development programs including an allosteric BCR-ABL inhibitor, a small-molecule GLP-1 receptor agonist, a THR-β agonist, and a preclinical GIPR modulator program. For more information, please visit: www.ternspharma.com. Cautionary Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements about the Company within the meaning of the federal securities laws, including those related to expectations, timing and potential results of the clinical trials and other development activities of the Company and its partners; the potential indications to be targeted by the Company with its small-molecule product candidates; the therapeutic potential of the Company’s small-molecule product candidates; the potential for the mechanisms of action of the Company’s product candidates to be therapeutic targets for their targeted indications; the potential utility and progress of the Company’s product candidates in their targeted indications, including the clinical utility of the data from and the endpoints used in the Company’s clinical trials; the Company’s clinical development plans and activities, including the results of any interactions with regulatory authorities on its programs; the Company’s expectations regarding the profile of its product candidates, including efficacy, tolerability, safety, metabolic stability and pharmacokinetic profile and potential differentiation as compared to other products or product candidates; the Company’s plans for and ability to continue to execute on its current development strategy, including potential combinations involving multiple product candidates; the Company’s plans and expectations around the addition of key personnel; and the Company’s expectations with regard to its cash runway and sufficiency of its cash resources. All statements other than statements of historical facts contained in this press release, including statements regarding the Company’s strategy, future financial condition, future operations, future trial results, projected costs, prospects, plans, objectives of management and expected market growth, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “positioned,” “potential,” “predict,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. The Company has based these forward-looking statements largely on its current expectations, estimates, forecasts and projections about future events and financial trends that it believes may affect its financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. These statements are subject to risks and uncertainties that could cause the actual results and the implementation of the Company’s plans to vary materially, including the risks associated with the initiation, cost, timing, progress, results and utility of the Company’s current and future research and development activities and preclinical studies and clinical trials. These risks are not exhaustive. For a detailed discussion of the risk factors that could affect the Company’s actual results, please refer to the risk factors identified in the Company’s SEC reports, including but not limited to its Annual Report on Form 10-K for the year ended December 31, 2023. Except as required by law, the Company undertakes no obligation to update publicly any forward-looking statements for any reason. Contacts for Terns InvestorsJustin Nginvestors@ternspharma.com MediaJenna UrbanBerry & Company Public Relationsmedia@ternspharma.com