TREM2

Alzheimer’s disease medicines commercialized in the past two years validated amyloid beta as a drug target, but these antibody therapies still have a hard time penetrating the membrane that covers blood vessels supplying the brain. AbbVie aims to best those drugs through its acquisition of Aliada Therapeutics, a clinical-stage biotech whose technology enables large molecules such as antibodies to cross this protective barrier. AbbVie announced Monday it is paying $1.4 billion in cash to acquire Aliada, a biotech that just entered the clinic earlier this year. Boston-based Aliada gets drugs across the blood-brain barrier (BBB) by leveraging receptors that transport substances into the brain. Lead Aliada program ALIA-1758 is an antibody engineered with binders for transferrin, which transports iron into the brain, and CD98, which transports certain amino acids. The drug comes from a platform technology called Modular Delivery, or MODEL. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health “We’re essentially taking advantage of normal physiological brain transport processes, and if you like, we’re hijacking those by attaching therapeutic cargos to our delivery modules to allow brain delivery,” Aliada Chief Scientific Officer John Dunlop explained in an interview during the BIO Conference in June. Aliada licensed MODEL from Johnson & Johnson subsidiary Janssen, which had used the technology to develop ALIA-1758. Aliada co-founder Danielle Feldman, who is senior director of corporate development for the company, was with RA Capital Management when her search for new technologies led her to Johnson & Johnson Innovation—JJDC, Dunlop said. Those discussions led both parties to conclude that the best way for the MODEL technology to realize its value was as a standalone company undistracted by the goings-on of a big pharmaceutical company. Aliada was formed at the end of 2021, with seed financing from RA Capital and J&J. OrbiMed and Sanofi Ventures later joined an extension of the financing. Dunlop declined to disclose how much was invested, but securities filings show the company raised $1 million in 2021, followed by nearly $32 million in late 2022. Dunlop did say Aliada had enough capital to support the lead program through Phase 1b proof-of-concept testing in Alzheimer’s. Clinical trial records show a Phase 1 trial began in May with a targeted enrollment of 52 healthy adults. According to Dunlop, ALIA-1758’s affinity for its target receptors means that more drug can get into the brain per dose, which should translate to needing a lower dosage level to achieve the desired therapeutic effect. A lower dose could reduce the adverse effects associated with amyloid-reducing drugs. Eisai’s Leqembi, which won full FDA approval last year, and Eli Lilly’s Kisunla, approved in July, carry warnings on their labels for risks of bleeding and swelling complications. presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB AbbVie has been spreading its bets in Alzheimer’s drug R&D. The company earlier this year reportedly discontinued development of ABBV-916 as a monotherapy, but is still leaving the door open for applications of the antibody as part of combination treatments. An Alzheimer’s partnership with Alector began in 2017. Two years ago, AbbVie terminated one program that had reached Phase 1 testing, opting to focus the alliance’s efforts on a second Alector program, AL002. This drug is an antibody designed to modulate the TREM2 receptor as a way of enhancing the activity of microglia, immune cells found in the central nervous system (CNS). Alector is responsible for Phase 1 and 2 testing, after which AbbVie has the option to license the drug. AbbVie’s pipeline currently shows AL002 is still in Phase 2 testing. In 2022, AbbVie paid $130 million up front to acquire Syndesi Therapeutics, developer of small molecule drugs that modulate synaptic transmission. Syndesi’s most advanced program, renamed ABBV-552, targets synaptic vesicle protein 2A (SV2A). AbbVie’s pipeline currently shows this program is in Phase 2 testing. AbbVie said it expect to close the Aliada acquisition by the end of this year. In the company’s announcement of the deal, Roopal Thakkar, executive vice president, research and development and chief scientific officer, AbbVie, said neuroscience is one of the company’s key growth areas. “This acquisition immediately positions us to advance ALIA-1758, a potentially best-in-class disease-modifying therapy for Alzheimer’s disease,” he said. “In addition, Aliada’s novel BBB-crossing technology strengthens our R&D capabilities to accelerate the development of next-generation therapies for neurological disorders and other diseases where enhanced delivery of therapeutics into the CNS is beneficial.”

SOUTH SAN FRANCISCO, Calif., Aug. 01, 2024 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (Nasdaq: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases, today reported financial results for the second quarter ended June 30, 2024, and provided business highlights. "In the second quarter, our Enzyme Transport Vehicle franchise gained additional momentum with continued engagement with the FDA on an accelerated approval pathway for tividenofusp alfa (DNL310, ETV:IDS) in MPS II and the FDA's selection of DNL126 (ETV:SGSH) in MPS IIIA for the START program," said Ryan Watts, Ph.D., Chief Executive Officer of Denali Therapeutics. “Today, we are also pleased to share that we have regained the rights to our TfR-based ATV:Abeta program from Biogen, thereby expanding our opportunities for addressing Alzheimer's disease with a potential best-in-class approach. We look forward to continuing to make significant progress as leaders in the promising and growing field of BBB-crossing therapeutics." Second Quarter 2024 and Recent Program Updates Late-stage and mid-stage clinical programs Tividenofusp alfa (DNL310): Enzyme Transport Vehicle (ETV)-enabled, iduronate-2-sulfatase (IDS) replacement therapy in development for MPS II (Hunter syndrome) In April, completed enrollment of 47 participants with MPS II in the Phase 1/2 open-label study.COMPASS, the global Phase 2/3 study, is expected to complete enrollment in 2024.In July, Molecular Genetics and Metabolism published a review co-authored by Denali's Chief Medical Officer, Carole Ho, M.D., titled, "Community consensus for heparan sulfate as a biomarker to support accelerated approval in neuronopathic mucopolysaccharidoses", which summarizes many of the presentations at the Reagan-Udall Foundation workshop held in February 2024 and provides a perspective on the path forward for neuronopathic MPS disorders.Following the Reagan-Udall Foundation workshop, Denali received written communication from the Center for Drug Evaluation and Research (CDER) division of the FDA indicating openness to discussing an accelerated approval pathway for tividenofusp alfa in MPS II with cerebrospinal fluid heparan sulfate (CSF HS) as a surrogate biomarker. Denali looks forward to continued engagement with CDER regarding Denali’s intention to file for approval of tividenofusp alfa using the accelerated approval pathway. Denali will provide an update in 2H 2024. DNL343: eIF2B activator in development for the treatment of amyotrophic lateral sclerosis (ALS) In May, the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) in collaboration with the Northeast ALS Consortium (NEALS) announced that enrollment is complete in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial. SAR443820/DNL788: CNS-penetrant RIPK1 inhibitor in development for the treatment of multiple sclerosis (MS) Sanofi is evaluating SAR443820/DNL788 in a Phase 2 study in participants with MS, which is fully enrolled. BIIB122/DNL151: LRRK2 inhibitor in development for the treatment of Parkinson’s disease (PD) Biogen is conducting the ongoing global Phase 2b LUMA study of BIIB122 in participants with early-stage Parkinson’s disease.Denali plans to initiate a global Phase 2a study in 2024 to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2. This study is being funded under the Collaboration and Development Funding Agreement with a third party. Eclitasertib (SAR443122/DNL758): Peripheral RIPK1 inhibitor in development for the treatment of ulcerative colitis (UC) Sanofi is conducting the ongoing Phase 2 study of SAR443122/DNL758 in participants with UC. Early-stage clinical and preclinical programs DNL126: ETV-enabled N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy in development for the treatment of MPS IIIA (Sanfilippo syndrome Type A) In June, Denali announced that the CDER selected DNL126 for participation in the FDA's Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program to further accelerate the development of novel drug and biological products for rare diseases. Participation in START is expected to facilitate and accelerate development of DNL126.Phase 1/2 biomarker and safety data are expected by the end of 2024. TAK-594/DNL593: Protein Transport Vehicle (PTV)-enabled progranulin (PGRN) replacement therapy in development for the treatment of frontotemporal dementia-granulin (FTD-GRN) Denali has finalized the protocol amendment for the Phase 1/2 study and prescreening of participants for Cohort B2 is ongoing. Oligonucleotide Transport Vehicle (OTV) platform Denali is advancing OTV:MAPT, targeting tau for Alzheimer’s disease, and OTV:SNCA, targeting alpha-synuclein for Parkinson’s disease, in the investigational new drug (IND)-enabling stage of development. Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program Today, Denali also announced that Biogen terminated its license to the ATV:Abeta program enabled by Denali’s TfR-targeting technology against amyloid beta for the potential treatment of Alzheimer's disease and granted Denali rights to data generated during the collaboration. As a result of the termination, all rights to develop, manufacture, perform medical affairs activities, and commercialize new TfR-targeting ATV:Abeta therapeutics reverted to Denali. Biogen licensed Denali's TfR-targeting ATV:Abeta program in April 2023 having exercised an option that was part of the 2020 collaboration agreement between the two companies. Biogen’s decision was not related to any efficacy or safety concerns with the Transport Vehicle platform.Denali is working to develop the next generation of anti-amyloid beta therapeutics with ATV:Abeta, which is designed to increase exposure of the therapeutic antibody and achieve broad biodistribution in the brain with the potential for improved efficacy and safety. Preclinical data demonstrated potential for a wider therapeutic window compared to a standard antibody, with superior plaque decoration and reduction and very low rates of amyloid related imaging abnormalities (ARIA). These data are included in a recent manuscript posted on bioRxiv.Denali plans to advance a TfR-targeting ATV:Abeta molecule as well as a CD98hc-targeting ATV:Abeta molecule into development for Alzheimer's disease. Discovery programs Denali applies its deep scientific expertise in neurodegeneration biology and the BBB to discover and develop medicines and platforms with the focus on programs enabled by the TV technology and targeting neurodegenerative disease, including Alzheimer’s and Parkinson’s, and lysosomal storage diseases. In July, Denali posted the manuscript titled, "Fc-engineered large molecules targeting the blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution compared to standard antibodies" on bioRxiv. Using comprehensive and unbiased approaches, Denali scientists reveal distinct biodistribution of the TfR and CD98hc transport vehicle delivery platforms from the brain single-cell level all the way to the whole body. Participation in Upcoming Investor Conferences BTIG Virtual Biotechnology Conference, August 5-62024 Wedbush PacGrow Healthcare Conference, August 13-14Morgan Stanley 22nd Annual Global Healthcare Conference, September 4-6H.C. Wainwright 26th Annual Global Investment Conference, September 9-112024 Cantor Global Healthcare Conference, September 17-19 Second Quarter 2024 Financial Results Net loss was $99.0 million for the quarter ended June 30, 2024, compared to net income of $183.4 million for the quarter ended June 30, 2023. There was no collaboration revenue for the quarter ended June 30, 2024, compared to $294.1 million for the quarter ended June 30, 2023. The decrease in collaboration revenue was primarily due to $293.9 million of revenue recognized in the quarter ended June 30, 2023 as a result of Biogen exercising their option to license our ATV:Abeta program. Total research and development expenses were $91.4 million for the quarter ended June 30, 2024, compared to $97.5 million for the quarter ended June 30, 2023. The decrease of approximately $6.1 million for the quarter ended June 30, 2024 was primarily attributable to a decrease in personnel and external expenses associated with the divestiture of the Company's preclinical small molecule programs. There were also decreases in external expenses associated with the ATV:TREM2 and PTV:PGRN programs due to the discontinuation of clinical development of TAK-920/DNL919 (ATV:TREM2) in Alzheimer’s disease and voluntary pause of Part B in the TAK-594/DNL593 (PTV:PGRN) Phase 1/2 study, respectively. Additionally, the Company commenced recognition of research funding for the LRRK2 program from the Collaboration and Development Funding Agreement executed in January 2024. These decreases were partially offset by increases in costs in various clinical stage programs, including eIF2B, ETV:SGSH and ETV:IDS reflecting the continued progress of these programs in clinical trials. General and administrative expenses were $25.2 million for the quarter ended June 30, 2024, compared to $26.1 million for the quarter ended June 30, 2023. The decrease of $0.9 million for the quarter ended June 30, 2024 was primarily attributable to a decrease in personnel-related expenses consisting of employee compensation and stock-based compensation expense, partially offset by combined increases of $0.2 million in professional services, facilities and other corporate costs. Cash, cash equivalents, and marketable securities were approximately $1.35 billion as of June 30, 2024. About Denali Therapeutics Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB, and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding expectations regarding Denali’s TV technology platform; statements made by Denali’s Chief Executive Officer; plans, timelines, and expectations regarding DNL310 and the ongoing Phase 2/3 COMPASS and Phase 1/2 studies, the timing and likelihood of accelerated approval, and the timing and availability of program updates; plans and timelines regarding DNL343, including in Regimen G of the Phase 2/3 HEALEY ALS Platform Trial; plans, timelines, and expectations of both Denali and Sanofi regarding DNL788, including the Phase 2 study in MS; plans, timelines, and expectations regarding DNL151, including with respect to the ongoing LUMA study as well as enrollment and timing of the proposed Phase 2a study in PD patients with LRRK2 mutations; expectations regarding DNL758, including the ongoing Phase 2 study in patients with UC; plans, timelines, and expectations related to DNL126, including the timing and availability of data in the ongoing Phase 1/2 study and the impact on development of participation in START; plans, timelines, and expectations of both Denali and Takeda regarding DNL593 and the ongoing Phase 1/2 study; plans, timelines, and expectations regarding the advancement of OTV:MAPT and OTV:SNCA towards clinical development; plans, timelines, and expectations regarding the ATV:Abeta program, including its therapeutic potential and the clinical advancement of ATV:Abeta molecules; plans and expectations for Denali's preclinical programs; Denali's future operating expenses and anticipated cash runway; Denali's PIPE financing and its anticipated proceeds; and Denali's participation in upcoming investor conferences. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: any and all risks to Denali’s business and operations caused by adverse economic conditions; risk of the occurrence of any event, change, or other circumstance that could give rise to the termination of Denali’s agreements with Sanofi, Takeda, or Biogen, or any of Denali’s other collaboration agreements; Denali’s transition to a late-stage clinical drug development company; Denali’s and its collaborators’ ability to complete the development and, if approved, commercialization of its product candidates; Denali’s and its collaborators’ ability to enroll patients in its ongoing and future clinical trials; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; Denali’s dependence on successful development of its blood-brain barrier platform technology and its programs and product candidates; Denali’s and its collaborators' ability to conduct or complete clinical trials on expected timelines; the risk that preclinical profiles of Denali’s product candidates may not translate in clinical trials; the potential for clinical trials to differ from preclinical, early clinical, preliminary or expected results; the risk of significant adverse events, toxicities or other undesirable side effects; the uncertainty that product candidates will receive regulatory approval necessary to be commercialized; Denali’s ability to continue to create a pipeline of product candidates or develop commercially successful products; developments relating to Denali's competitors and its industry, including competing product candidates and therapies; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates; implementation of Denali’s strategic plans for its business, product candidates, and blood-brain barrier platform technology; Denali's ability to obtain additional capital to finance its operations, as needed; Denali's ability to accurately forecast future financial results in the current environment; and other risks and uncertainties, including those described in Denali's most recent Annual and Quarterly Reports on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 28, 2024 and May 7, 2024, respectively, and Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward-looking statements, to conform these statements to actual results, or to make changes in Denali’s expectations, except as required by law. Denali Therapeutics Inc.Condensed Consolidated Statements of Operations(Unaudited)(In thousands, except share and per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023Collaboration revenue: Collaboration revenue from customers(1)$— $294,123 $— $329,264 Total collaboration revenue — 294,123 — 329,264 Operating expenses: Research and development(2) 91,399 97,520 198,415 226,336 General and administrative 25,194 26,120 50,430 53,260 Total operating expenses 116,593 123,640 248,845 279,596 Gain from divestiture of small molecule programs — — 14,537 — Income (loss) from operations (116,593) 170,483 (234,308) 49,668 Interest and other income, net 17,567 12,900 33,480 23,934 Net income (loss)$(99,026) $183,383 $(200,828) $73,602 Net income (loss) per share: Net income (loss) per share, basic$(0.59) $1.34 $(1.26) $0.54 Net income (loss) per share, diluted$(0.59) $1.30 $(1.26) $0.52 Weighted-average shares used in calculating: Net income (loss) per share, diluted 168,831,329 137,047,227 159,117,759 136,787,321 Weighted average number of shares outstanding, basic and diluted 168,831,329 140,930,625 159,117,759 140,550,226 __________________________________________________(1) Includes related-party collaboration revenue from customers of $294.1 million and $294.3 million for the three and six months ended June 30, 2023, respectively.(2) Includes expenses for cost sharing payments due to a related party of $7.0 million and $11.1 million for the three and six months ended June 30, 2023, respectively. Denali Therapeutics Inc.Condensed Consolidated Balance Sheets(Unaudited)(In thousands) June 30, 2024 December 31, 2023Assets Current assets: Cash and cash equivalents$74,679 $127,106 Short-term marketable securities 821,365 907,405 Prepaid expenses and other current assets 32,339 29,626 Total current assets 928,383 1,064,137 Long-term marketable securities 450,994 — Property and equipment, net 48,077 45,589 Operating lease right-of-use asset 24,533 26,048 Other non-current assets 50,578 18,143 Total assets$1,502,565 $1,153,917 Liabilities and stockholders' equity Current liabilities: Accounts payable$13,936 $9,483 Accrued clinical and other research & development costs 19,915 19,035 Accrued manufacturing costs 7,111 15,462 Other accrued costs and current liabilities 6,013 5,152 Accrued compensation 9,555 21,590 Operating lease liability, current 7,771 7,260 Deferred research funding liability 10,232 — Total current liabilities 74,533 77,982 Operating lease liability, less current portion 40,981 44,981 Total liabilities 115,514 122,963 Total stockholders' equity 1,387,051 1,030,954 Total liabilities and stockholders’ equity$1,502,565 $1,153,917 Investor and Media Contact: Laura Hansen, Ph.D.Vice President, Investor Relations(650) 452-2747hansen@dnli.com

Pictured: A brain hovers over a hand against a yellow-striped background/Taylor Tieden for BioSpace The first half of 2024 was filled with ups and downs for patients and researchers in the neurological disease space. The amyotrophic lateral sclerosis community took a hit when Amylyx’s Relyvrio failed its confirmatory Phase III trial and was subsequently withdrawn from the market. Huntington’s disease patients saw new hope in the form of positive mid-stage data from Wave Life Sciences. The second half of the year kicked off with the approval of a novel disease-modifying treatment for Alzheimer’s disease, only the second such option now available to patients. The next six months are shaping up to be just as eventful in clinical research, with key data readouts expected in Alzheimer’s, schizophrenia, depression and a couple of rare diseases. Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, noted several key upcoming data readouts in both the neuropsychiatric and neurodegenerative spaces. Here are five BioSpace is keeping a close eye on. Athira Pharma’s Fosgonimeton Alzheimer’s disease Recently approved medicines Leqembi and Kisunla command the most attention in the Alzheimer’s disease treatment space as the first anti-amyloid antibodies on the market, but the experimental Alzheimer’s pipeline is still robust. One candidate with a different mechanism of action is fosgonimeton, currently in a Phase II/III trial. Topline data from the trial, which includes around 550 patients, are expected in the second half of this year. Developed by Athira Pharma, fosgonimeton is designed to modulate the HGF/MET system to activate neuroprotective and anti-inflammatory pathways in the central nervous system. Athira presented data from the Phase II SHAPE trial in Parkinson’s disease dementia and dementia with Lewy bodies at the AD/PD 2024 International Conference in March, showing “encouraging safety and pro-cognitive measures.” These results “underscore confidence” in the Phase II/III LIFT-AD trial in Alzheimer’s disease, according to the company’s press release. In 2022, fosgonimeton combined with standard-of-care acetylcholinesterase inhibitors missed the primary endpoint in Athira’s Phase II ACT-AD study, failing to best placebo in ERP P300 latency, a measure of working memory processing speed. However, a planned analysis of subgroup data showed cognitive and functional improvements through the drug’s modulation of the HGF/MET system, and Athira moved forward investigating fosgonimeton as a monotherapy for Alzheimer’s. AbbVie/Cerevel’s Emraclidine Schizophrenia In December 2023, AbbVie invested nearly $9 billion in the schizophrenia space with the acquisition of Cerevel Therapeutics and its late-stage asset emraclidine. (This deal has not yet closed.) Later this year, the company will learn whether its investment has paid off. Two Phase II trials, EMPOWER-1 and EMPOWER-2, comprise approximately 750 individuals in total and are projected to read out by the end of 2024. In these trials, AbbVie is seeking the rapid improvement of schizophrenia symptoms. The trials’ primary endpoint is change from baseline after six weeks on the Positive and Negative Syndrome Scale (PANSS) scale. The studies are also evaluating the safety and tolerability of emraclidine, a positive allosteric modulator of the muscarinic M4 receptor. AbbVie will need strong data from the EMPOWER trials to keep pace with Bristol Myers Squibb, which is expecting an FDA decision in September on its own novel schizophrenia treatment, KarXT, which also targets the M4 as well as M1 muscarinic receptors. BMS obtained KarXT in its December acquisition of Karuna Therapeutics. “[Emraclidine] is behind,” Suvannevejh said. “Cerevel knew that they needed to play catch-up versus Karuna,” so they tried to design the Phase II studies to be large enough and robust enough to be considered by the FDA as Phase III studies. “We don't know if FDA is going to agree to that, [but] that’s what their hope is going to be.” Neumora Therapeutics’ Navacaprant Major depressive disorder Also in the neuropsychiatric space, Watertown, Mass.–based Neumora Therapeutics is expecting the first Phase III data for its lead asset navacaprant, a Kappa-opioid receptor (KOR) antagonist in development for major depressive disorder (MDD), in the fourth quarter of this year. The KOR system is a “well-characterized pathway known to mediate depressive-like states, and modulating this system represents a novel approach to treating MDD and other major neuropsychiatric disorders,” according to Neumora’s website. Mizuho is “bullish” on navacaprant’s prospects, due to “de-risking” Phase II data, validation from a competitor program, a positive reception from key opinion leaders on the KOR class and a large, addressable MDD market, Suvannevejh wrote in a July 8 investor note. “This represents a brand-new class for depression,” Suvannevejh said, adding that there is a “fair amount of industry excitement” around KOR antagonists due to the less-than-ideal side effects associated with currently marketed antidepressants. Neumora launched the Phase III trial in July 2023 after navacaprant monotherapy demonstrated “statistically significant and clinically meaningful reductions in symptoms of depression and anhedonia” in Phase II trial participants with moderate-to-severe MDD. If these studies are successful, Neumora intends to New Drug Application with the FDA for navacaprant in 2025. Amylyx’s AMX003 Wolfram syndrome A week after announcing the voluntary withdrawal of recently approved ALS treatment Relyvrio (AMX0035) from the U.S. and Canadian markets, Amylyx received a glimmer of hope for the drug—a combination of sodium phenylbutyrate and taurursodiol—in another neurodegenerative condition: Wolfram syndrome. Wolfram syndrome is characterized by childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy, with many patients also developing diabetes insipidus, sensorineural hearing loss and autonomic nervous system degeneration. The multi-organ disease is caused by mutations in the WFS1 gene that lead to endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which causes “lack of function across many different cell types, and ultimately, cell death across multiple cell types, starting with beta cells in the pancreas and then moving to parts of the nervous system,” explained Justin Klee, co-CEO of Amylyx. “AMX0035 targets ER stress and mitochondrial dysfunction.” Interim results from the ongoing Phase II HELIOS trial showed AMX0035 improved pancreatic function and glycemic control in adult patients with the rare, inherited disease. Treatment with Amylyx’s drug led to an increase in total C-peptide response, an established marker of pancreatic beta cell function and glycemic control and the trial’s primary efficacy measure. With these data, from eight patients who had completed 24 weeks of treatment, Amylyx co-CEO Josh Cohen told BioSpace that the company plans to engage with regulators on a possible development path for AMX0035 in Wolfram syndrome. Amylyx expects topline data from all 12 trial participants after 24 weeks of treatment during the second half of 2024. Vigil Neuroscience’s Iluzanebart ALSP Another company anticipating mid-stage data for a rare disease candidate is Vigil Neuroscience. Vigil is developing iluzanebart for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), an inherited, autosomal dominant neurological disease affecting approximately 10,000 people in the U.S. Phase II data are expected in the third quarter of 2024. ALSP is caused by loss-of-function mutations in the CSF1R gene, leading to microglial dysfunction. Iluzanebart is designed to increase signaling through DAP12/SYK to mitigate microglial dysfunction, according to Vigil. In preclinical studies, iluzanebart has “demonstrated sub-nanomolar potency and selective target engagement with TREM2,” which activates the cascade of downstream signals to mediate neuroprotective and homeostatic functions of the microglia. “It's important for Vigil and it's important for patients with this disease because there are no FDA-approved treatments . . . and Vigil is the only game in town for this disease,” Suvannevejh said. “It’s a very novel agent targeting this TREM2 mechanism of action,” and for investors, the jury is still out on whether this is an effective approach, he said. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.