KHK

After years of clinical failures and FDA rejections in the liver disease space, Madrigal Pharmaceuticals has finally taken gold in the race for the first approval in metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH). Specifically, the FDA granted Rezdiffra (resmetirom) accelerated approval to treat adults with non-cirrhotic MASH and moderate-to-advanced liver fibrosis consistent with stages F2 to F3 fibrosis, in conjunction with diet and exercise. A biopsy is not required for diagnosis.The THR-β selective agonist will be available to US patients starting April, after months of building excitement. In a 70-physician FirstWord poll conducted last month, 30% of respondents said they were very enthusiastic about prescribing the drug (see: Physician Views Results: Potential new NASH drug gets positive assessment from US docs).This greenlight will most likely open the MASH floodgates. Despite the difficulty designing drugs for the heterogeneous liver disease, which has a variety of etiologies and paths of progression, a series of promising candidates across multiple mechanisms have lined up behind Rezdiffra, such as FGF21 analogues and GLP-1 agonists. For more on the development landscape, see Spotlight On: MASH pipeline holds promise of multiple mechanisms for disease management.Rezdiffra’s approval comes, in part, because it was able to demonstrate efficacy without the safety concerns that sunk Intercept Pharmaceuticals’ obeticholic acid. Treatment defining dataRezdiffra, a once-daily, oral candidate secured FDA approval on Thursday thanks to 52-week data from the pivotal MAESTRO-NASH study, which met the co-primary endpoints of MASH resolution with no worsening of fibrosis, and at least a one-stage reduction in fibrosis with no worsening of non-alcoholic fatty liver disease (NAFLD) activity score. According to results, 25.9% of patients who received the 80mg dose, and 29.9% in the 100mg arm, achieved MASH resolution endpoint, compared with 9.7% for placebo. For fibrosis improvement, the rates were 24.2% and 25.9% for the low- and high-dose arms, respectively, versus 14.2% for placebo.Most of the reported side effects were mild-to-moderate, with a roughly 11-13% serious adverse event rate across each of the three cohorts. There was no incidence of drug-induced liver injury, increases in bone fractures or adverse events linked to thyroid hormone effects outside the liver such as heart rate changes.Rezdiffra’s label reflects the clinical safety results. The drug does not carry a boxed warning, and its label notes that the most common side effects are diarrhoea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness.First success of many failuresMadrigal’s journey to FDA approval comes after the failures of several other drug developers to show both safety and efficacy of their MASH programmes, most notably that of obethicholic acid from Intercept.The biotech received its first complete response letter for the candidate in 2020, which said that the predicted benefit of obethicholic acid "does not sufficiently outweigh the potential risks.” Three years later, FDA again rejected the treatment, saying that approval would require, at a minimum, the successful completion of a long-term outcomes Phase III trial.Large pharmas have also seen their fair share of setbacks in the disease. Last year, Novartis ended a partnership with Pliant Therapeutics to develop the latter's integrin αVβ1 inhibitor PLN-1474 for MASH.Pfizer and AstraZeneca have both recently trimmed their MASH pipelines. The UK drugmaker terminated development of late-stage injectable GLP-1/glucagon co-agonist cotadutide last year, while the US pharma has ended at least two MASH programmes in the last three years: ketohexokinase inhibitor PF-06835919, and oral GLP-1 receptor agonist danuglipron. MASH future looks brightNow that Madrigal has shown approval is possible, drugmakers waiting in the wings may be more bullish on the prospects for their own programmes. FirstWord spoke with 89bio chief medical officer Hank Mansbach earlier this week on the chances of accelerated approval for FGF21 analogue pegozafermin, for which it just launched a Phase III trial. At the time, Mansbach said an approval for resmetirom would give the company a confidence boost. Other companies who have shared promising mid-stage data include fellow FGF21 developer Akero Therapeutics, Ionis Pharmaceuticals’ antisense inhibitor, Sagimet Biosciences and its fatty acid synthase (FASN) inhibitor, partners Boehringer Ingelheim and Zealand Pharma for their dual GLP-1 and glucagon agonist, as well as Viking Therapeutics, whose candidate has the same mechanism of action as Madrigal’s.

Eli Lilly remains in the nonalcoholic steatohepatitis race even after its retreat from KHK. Eli Lilly’s second stab at developing a KHK inhibitor in diabetes and nonalcoholic steatohepatitis (NASH) is over. Fifteen months after dropping its first candidate, Lilly has kicked the second program from its phase 1 pipeline, dealing another blow to a target that has attracted the attention of Pfizer. KHK, also known as ketohexokinase, modulates the effect fructose has on human metabolism. Inhibiting the enzyme could cut the amount of sugar that is converted into fat and the amount of fat that is stored in the liver, thereby potentially lowering the risk of NASH development, treating symptoms and providing weight benefits.  Pfizer has led the way in the space, moving a KHK inhibitor, PF-06835919, into the clinic in 2016 and going on to link the molecule to significant reductions in whole liver fat in a midphase study. But Lilly has stayed tucked in behind its rival and at one point had two KHK inhibitors in phase 1 development.  The first program fell in October 2021, and it has now been joined in Lilly’s discard pile by KHK inhibitor No. 2. Lilly disclosed the removal of the one-time potential treatment of diabetes and NASH from its pipeline in its fourth-quarter results update. The removal ends a program that Lilly supported through projects such as an assessment of the prevalence of KHK gene variants and a patent filing for pyrazole compounds. Lilly’s retreat from KHK inhibition leaves the future of the target in doubt. Pfizer ran a series of phase 1 and 2 clinical trials of PF-06835919 between 2016 and 2021, and included the asset in its NASH tie-up with Novartis in 2018. But the only study to start since 2020 is a 17-subject phase 2 trial sponsored by Maastricht University Medical Center.  The wind down in KHK inhibitor clinical trial activity dampens the chances of the target helping to unlock the NASH market, which lost some of its luster in recent years as programs across the industry have hit setbacks. Lilly remains in the race even after its retreat from KHK. Like peers such as Amgen, AstraZeneca and Johnson & Johnson, Lilly is targeting PNPLA3, and it is also studying tirzepatide in NASH.

– Company Expects to Initiate a Phase 1/2 Study for ALN-KHK in Early 2023, with Initial Results Expected in Late 2023 – CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals Inc. (Nasdaq: ALNY), the leading RNAi (RNA interference) therapeutics company, announced today that the Company has submitted a Clinical Trial Authorization (CTA) application to Health Canada to initiate a Phase 1/2 study of ALN-KHK, an investigational RNAi therapeutic targeting ketohexokinase (KHK) for the treatment of Type 2 diabetes mellitus (T2DM). Pending regulatory authority and ethic committee approvals, the Company plans to begin enrollment in a Phase 1/2 study in healthy overweight to obese volunteers and obese patients with T2DM in early 2023, and expects to report initial human data in late 2023. “We are excited to advance ALN-KHK to the clinic as our first RNAi therapeutic to address the unmet medical need in Type 2 diabetes mellitus and potentially other metabolic disorders,” said Neil Wallace, Program Leader for the ALN-KHK program at Alnylam. “Increased dietary fructose consumption, largely resulting from use of high-fructose corn syrup as a sweetener, is believed to contribute to the growing pandemic of obesity. Obesity is a significant risk factor for both T2DM and fatty liver disease. Fructose itself predisposes to fatty liver disease and thus, in the context of T2DM, aggravates insulin resistance. We believe targeting ketohexokinase, also known as fructokinase, the first enzyme in the pathway of fructose metabolism, is a novel therapeutic approach to reduce fatty acid synthesis and insulin resistance, with the potential to improve overall glycemic control in individuals with T2DM.” ALN-KHK is a wholly-owned asset in the Alnylam clinical development portfolio. About ALN-KHK ALN-KHK is an investigational, subcutaneously administered RNAi therapeutic targeting ketohexokinase for the treatment of Type 2 diabetes mellitus (T2DM). ALN-KHK utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index. The safety and efficacy of ALN-KHK have not been evaluated by the FDA, EMA, Health Canada, or any other health authority. About Type 2 Diabetes Mellitus Type 2 Diabetes Mellitus (T2DM) is a global disease affecting more than 6% of the world’s population. Its incidence and prevalence rates are believed to be increasing worldwide with estimates of more than 450 million affected. The prevalence of diabetes is expected to reach 55 million within the US by 2030. Management of T2DM is aimed at achieving a target hemoglobin A1c levels (a measure of blood sugar) of less than 7%. Typically diet and exercise are recommended with the aim of achieving weight loss; this is rarely successful. Despite a number of treatment options, many patients do not reach adequate blood sugar control. There is an unmet need for a treatment that can produce sufficient glycemic control while providing simpler dosing administration and longer dosing intervals that could improve treatment compliance, thereby reducing disease complications and overall mortality. About RNAi RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam Pharmaceuticals (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding 20 years ago, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), AMVUTTRA® (vutrisiran) and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram. Alnylam Forward Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations beliefs, goals, plans or prospects, including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, and Alnylam’s projected commercial and financial performance, should be considered forward-looking statements. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition and the effectiveness or timeliness of Alnylam’s efforts to mitigate the impact of the pandemic; the potential impact of the January 2022 leadership transition on Alnylam’s ability to attract and retain talent and to successfully execute on its “Alnylam P5x25” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches, including using Alnylam’s IKARIA and GEMINI platforms, and successfully demonstrate the efficacy and safety of its product candidates, including ALN-KHK; the pre-clinical and clinical results for its product candidates, including ALN-KHK; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including ALN-KHK, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO or AMVUTTRA in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial pro the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. This press release discusses investigational RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. There is no guarantee that any investigational therapeutics will successfully complete clinical development or gain health authority approval.