Dexpramipexole Dihydrochloride

The new program's forthcoming database will fill in the knowledge gaps by first compiling existing data from various entities. In 2015, after spending nearly four decades grinding his way up the ladder at one of the world’s most prolific construction equipment companies, Ed Rapp was nearing its apex. He had risen from humble beginnings in a town of fewer than 800 people to presiding over Caterpillar Inc.’s massive Resource Industries division. He was in the running to become CEO.   Then the rug was pulled out from under him. Rapp was diagnosed with the incurable neurodegenerative disease amyotrophic lateral sclerosis—also known as ALS, or Lou Gehrig’s disease—and forced into early retirement.    “Thirty-seven years at Cat, you know, two sick days and 12 months from potentially being the CEO of the company, when you get an ALS diagnosis, and you’ve got two to five years to live,” he recalled to Fierce Biotech Research in an interview.   Rapp, 67, has clearly outlived that prognosis and has taken advantage of the extra time by channeling his ambition into the quest to find better therapies and diagnostic tools for ALS. Now, he’s co-chair of a working group in a new effort to change how the disease is diagnosed and treated: the Accelerating Medicines Partnership in Amyotrophic Lateral Sclerosis, or AMP ALS, a five-year, $60 million public-private partnership announced May 21 by Foundation for the National Institutes of Health (FNIH), an independent nonprofit that supports the work of the NIH. “This is the first time we’re going to have all the leading organizations working in ALS from the for-profit side and the non-profit side working together,” Alessio Travaglia, Ph.D. director of neuroscience at the FNIH, said. “That’s the main reason why this initiative is going to be so powerful.” Slow progress   Despite advances in research, therapies and massive awareness campaigns, the prognosis for ALS patients hasn’t moved much in the last few decades, Dave Shulman, 46, a Wells Fargo executive who was diagnosed with ALS in 2023, told FBR.  “[When I was first diagnosed,] I wondered, 'Why are we 10 years out from the Ice Bucket Challenge, over 80 years out from Lou Gehrig’s famous speech, and more than 150 years out from when ALS was first identified by a researcher, and we’re still not at a place where we can meaningfully slow, stop or reverse the disease?'” he said. “And what are the underlying reasons why so many ALS clinical trials fail?” Recent years have seen some big steps forward, like the 2023 FDA approval of Biogen and Ionis Pharmaceuticals’ Qalsody, or tofersen, which slows symptom progression in ALS patients with a mutation in the protein SOD-1. But that subgroup makes up just 2% of the disease population. The two drugs that are FDA-approved for all ALS patients, Covis Pharma’s Rilutek and Mitsubishi Tanabe’s Radicava, have only “modest” effects, according to James Berry, M.D., a neurologist and ALS researcher at Massachusetts General Hospital.  “We are lucky to be in an era when we have seen the development of newer more effective therapies for ALS than ever before,” Berry said in an email. But the tempered efficacy of ALS drugs that work across subtypes suggests that they might be acting on mechanisms that occur after damage-causing cascades are already underway, he explained, which limits how much of an impact they can have, even if they do apply to all patients.   Other major drawbacks, like the removal of Amylyx’s ALS drug Relyvrio from the market in April, underscore the challenge of developing ALS drugs.     “So, while we do have more treatment options today than we have ever had in the past, we still have a long way to go,” Berry said.   ALS is a complicated disease, to put it mildly. And while decades of research have lent insight into the basic mechanisms and the contribution of factors like SOD-1 mutations, there’s still a black box around its natural course and what kinds of biomarkers are associated with progression, Steph Fradette, vice president and head of neuromuscular development at Biogen and a steering committee member of AMP ALS, told FBR.   “The foundational challenge is that we’re still coming to understand the underlying pathophysiology of ALS,” she said. “There are exceptions to that rule and we are making a lot of progress as a field, but we still have a lot of uncertainty about what is actually causing the disease, what are the downstream implications of that cause and then, of course, how to address it.”   The win with Qalsody aside, Biogen like other companies has weathered its share of ALS drug failures, most recently with an Ionis-partnered candidate called BIIB105. That drug wasn’t as far along as the company’s first attempt at an ALS therapy—dexpramipexole—which failed a phase 3 trial in 2013, but it suffered from the same blind spots with regards to efficacy.  “Over the past several years we’ve found ourselves, like with dexpramipexole, in a situation where we have false positive and false negative trial results,” Fradette said. That has led to conversations within the field about what endpoints are really indicative of progress as well as about the tools used to measure them, she added. That’s not to say there’s been no improvements, of course: Qalsody was approved on the basis of reductions in a marker called plasma neurofilament light chain (NfL), a protein that is increasingly being used as an indicator of neuronal damage in neurological drug trials.    But it took longer to get NfL assays out of academic labs and into industry practice than if an initiative like AMP ALS had existed, Fradette said. And it’s hard to go further without knowing how the disease progresses naturally—which is impossible without biological samples from patients, both living and deceased. Although there are currently disparate efforts to collect these on the part of government and nonprofit organizations, there are still too few, Travaglia said.   “We don’t have enough post-mortem samples or longitudinal samples. We have to rely on just one single data point, meaning we take patients today and analyze those samples, but we don’t know how those biomarkers are going to progress,” he explained.   Beyond a shot in the dark     The ALS AMP’s database will fill in the knowledge gaps by first compiling existing data from various entities then getting more from patients and those at risk of ALS based on what’s missing. Seven biotechs, seven nonprofits and two government agencies—the FDA and the NIH's National Institute of Neurological Disorders and Stroke—are involved in the creation of the database. Representatives from the entities will sit on a steering committee that decides what information is needed, then the FNIH and NIH will put out requests for proposals and issue grants to researchers to collect it. “More than anything, I think that bringing together these different datasets and knowledge across the different people at the table will help accelerate that understanding in a way that anyone or group of us can do on our own,” Fradette said.   Besides identifying biomarkers and therapies that might be useful for ALS patients in general, the effort may also delineate groups of patients with certain genetic factors that cause them to develop ALS, like those with the SOD-1 mutation. This could eventually make it possible to treat ALS with personalized medicines like the ones used for cancer, Julie Gerberding, M.D., president and CEO of the FNIH, said in an email.  “The program will focus on comprehensive data collection and analysis that can help identify subgroups within the ALS population,” Gerberding said. “These subgroups might have distinct underlying causes that will allow researchers to develop targeted therapies specific to the subgroups.”  For Rapp, Shulman and many other patients who are involved in AMP ALS, progress can’t come soon enough.   “There is pretty good acceptance that ALS is not a single disease—it’s more like cancer where you have different variations,” Rapp said. “But until you understand that, I think any drug trials are a bit of a shot in the dark because you’ll never know if you have the right subgroup of patients.” Editor's note: This article was updated May 29 to clarify that the FNIH is an independent nonprofit and to update the number of biotechs, partners and nonprofits participating in AMP ALS, as well as to adjust some details about how the program works. Travaglia's last name was also misspelled in an earlier version and was corrected. 

One concern about the GLP-1 class of metabolic disorder drugs is that the weight patients lose includes muscle as well as fat. BioAge Labs wants to test whether its experimental medication, dosed alongside Eli Lilly’s weight management drug Zepbound, can preserve muscle mass. The startup recently closed $170 million to finance a mid-stage clinical trial. BioAge develops drugs that address aspects of human aging. Its lead drug candidate, azelaprag, is a small molecule designed to bind to and activate the apelin receptor, which regulates muscle metabolism, growth, and repair. This drug came from the labs of Amgen, which initially developed it for treating heart failure. Amgen’s Phase 1 tests showed the drug hit its target with a clean safety profile, BioAge CEO Kristen Fortney told MedCity News in a 2022 interview. But as a heart drug, the results were “not dramatic,” she said. Amgen elected to shelve the molecule. Richmond, California-based BioAge licensed it from the pharma giant in 2021, with the goal of testing it as a way of preserving muscle mass in elderly people. In BioAge’s Phase 1b study enrolling 21 participants age 65 and older, results showed the experimental drug led to statistically significant prevention of muscle atrophy relative to a placebo after 10 days of bed rest. The company planned to proceed to larger Phase 2 test enrolling intensive care unit patients, who can lose more than 15% of their muscle mass in just one week, according to published research. Last fall, BioAge announced the Phase 2 trial would go in a different direction. Instead of testing azelaprag in ICU patients, the trial will evaluate the drug alongside Eli Lilly’s Zepbound. The injectable drug, which activates the GLP-1 and GIP receptors, is an incretin mimetic, a type of drug that works by mimicking hormones found in the gut. The new clinical trial plan is based on preclinical research in obese mice. Results reported last year showed that treating the mice with both azelaprag and Lilly’s drug led to greater weight loss than what was achieved with the Lilly drug alone. The drug pairing also led to improvement in body composition and muscle function. Under a collaboration agreement, Lilly will supply Zepbound for BioAge’s trial, which will be run in collaboration with Chorus, a small independent clinical development organization within the pharma giant. BioAge adjusted its focus for azelaprag after the company’s technology uncovered new insight about the molecule. The BioAge discovery platform, built on analysis of human longevity data, identified a link between the apelin pathway activity and physical function during aging, Fortney said in an email. While the Phase 1b clinical trial led to results showing significant muscle and metabolic benefits in healthy elderly volunteers on bed rest, the molecule’s mechanism has multiple potential applications, Fortney said. “Obesity is the indication we are focusing on given the strong weight loss synergy we see preclinically with incretins,” she said. “This is an oral drug with the potential to increase weight loss quantity with a fully oral regimen, as well as to improve weight loss quality.” Fortney said BioAge will share more details on the design of the Phase 2 trial in the future, but the study will compare azelaprag (known at BioAge as BGE-105) in combination with Zepbound versus Zepbound alone. The primary endpoint will be weight loss. In addition, the company will monitor exploratory endpoints related to improvement of body composition—the balance of lean mass to fat mass. BioAge’s new capital will finance the planned Phase 2 test, which is on track to start in mid-2024. The Series D round was led by Sofinnova Investments. New investors joining the financing include Longitude Capital, RA Capital Management, Cormorant Asset Management, RTW Investments, SV Health Investors, OrbiMed Advisors, Sands Capital, Pivotal bioVenture Partners, Osage University Partners, Lilly Ventures, and Amgen Ventures. The latest round also included participation from earlier investor Andreessen Horowitz. Here’s a look at other recent life science industry financing activity: —Frontier Medicines, developer of targeted medicines for oncology and immunology, closed $80 million in financing to support its pipeline. The biotech’s most advanced program is FMC-376, which is in development for treating patients whose cancer is positive for KRAS G12C. This mutation was first drugged by Lumakras from Amgen and then Krazati from Mirati Therapeutics. Both drugs lock KRAS G12C protein in an inactive state. Frontier’s drug candidate is designed to block this cancer-driving protein in either its active or inactive states, potentially offering an option for patients who have not responded to the Amgen or Mirati drugs. In addition to supporting FMC-376, which recently dosed the first patient in a Phase 1/2 study, Frontier said the new capital will support other wholly owned programs in its pipeline. Deerfield Management Company and Droia Venture co-led the company’s Series C financing, which also included “significant participation” by Belgium-based drugmaker Galapagos. Frontier last raised money in 2021, an $88.5 million Series B round. —Firefly Bio revealed $94 million to finance R&D of degrader antibody conjugates, or DACs, which carry a protein degrader as the drug payload. In preclinical research, the biotech said its drugs led to “significant reduction of tumor volume at very low doses.” Firefly was incubated by Versant Ventures, which co-led the startup’s Series A financing with MPM BioImpact. —Roche, already an investor in liquid biopsy company Freenome, led an additional $254 million financing for the company. South San Francisco-based Freenome will apply the cash toward ongoing pivotal clinical trials evaluating its blood screening technology in colorectal cancer and lung cancer. The company is also conducting a study of its technology as a way to detect multiple cancers. Roche last invested in Freenome two years ago, a $290 million infusion that followed the company’s $300 million Series D financing. —Latigo Biotherapeutics launched with $135 million to finance clinical development of a non-opioid drug that blocks NaV1.8, a sodium channel associated with pain. It’s the same target addressed by a Vertex Pharmaceuticals drug candidate that recently posted data showing it met its main Phase 3 goal assessing pain relief compared to a placebo. But on a secondary goal of showing superiority to standard of care Vicodin, the Vertex drug came up short. Thousand Oaks, California-based Latigo claims its drug could be best in the class of NaV1.8 inhibitors with rapid onset, meaningful efficacy, and superior safety. It’s currently in Phase 1 testing. Latigo’s Series A financing was led by Westlake Village BioPartners, which incubated the startup. —Cancer immunotherapy developer NextPoint Therapeutics added $42.5 million to its Series B financing, bringing the round’s total to $122.5 million. The drugs of Cambridge, Massachusetts-based NextPoint target the HHLA2 pathway. NextPoint first announced its Series B round last year. —Sudo Biosciences expanded its Series B financing by $31 million, bringing the round’s total to $147 million. The new investors are Dementia Discovery Fund, Leaps by Bayer, and UPMC Enterprises. Carmel, Indiana-based Sudo emerged from stealth in 2022 to develop small molecule drugs that address TYK2, an autoimmune disease target first hit by the Bristol Myers Squibb drug Sotyktu. —Alys Pharmaceuticals launched with $100 million from Medicxi, the investment firm that formed the company. The preclinical biotech, which focuses on developing treatments for immune disorders of the skin, was formed by combining six Medicxi portfolio companies. Target indications include atopic dermatitis, vitiligo, psoriasis, and mastocytosis. —Antibody drug conjugate developer ProfoundBio closed $112 million in financing, which will be applied to clinical development of its pipeline. Lead program rinatbart sesuctecan, or Rina-S, targets folate receptor alpha, a validated cancer target. A pivotal Phase 1/2 study is underway in ovarian cancer. Ally Bridge Group led the Seattle-based biotech’s Series B round. ProfoundBio, whose management team brings experience from ADC specialist Seagen, emerged in 2021 backed by a $55 million Series A financing. —Areteia Therapeutics expanded its Series A round by $75 million with the addition of new investors Viking Global Investors and Marshall Wace. The Chapel Hill, North Carolina-based biotech’s Series A financing was announced at $350 million in 2022. Lead drug candidate dexpramipexole comes from the labs of Knopp Biosciences. Areteia is currently testing the molecule in three Phase 3 clinical trials enrolling patients with eosinophilic asthma, a severe form of asthma. —Basking Biosciences raised $55 million in a financing led by Arch Venture Partners. Columbus, Ohio-based Basking will use the capital to continue clinical development of BB-031, a potential treatment for acute ischemic stroke. The Basking drug is a reversible RNA aptamer designed to target von Willebrand factor, a clotting protein. BB-031 is engineered for both rapid onset and short duration of effect. Basking plans to start Phase 2 testing later this year. —Neurona Therapeutics, developer of regenerative medicines for neurological disorders, closed $120 million in financing. The San Francisco-based biotech makes cell therapies from human pluripotent stem cells, which have the ability to become almost any type of cell. Neurona will apply the capital toward ongoing Phase 1/2 testing of NRTX-1001, developed as a one-time treatment to silence epileptic seizures. Viking Global Investors and Cormorant Asset Management co-led Neurona’s Series E round. —Cour Pharmaceuticals has already out-licensed a celiac disease therapeutic candidate to Takeda Pharmaceuticals, which has advanced the nanoparticle-based therapy to Phase 2 testing. Chicago-based Cour wants to develop its own drug candidates and it raised $105 million to support programs in type 1 diabetes and myasthenia gravis. Lumira Ventures and Alpha Wave Ventures co-led the Series A financing, which included participation from three big pharma companies. —Eyconis, a new company formed with assets from Ascendis Pharma, launched with a $150 million financing commitment from an investor syndicate that includes Frazier Life Sciences, RA Capital Management, venBio, and HealthQuest Capital. Eyconis, which will operate from Redwood City, California, has ophthalmology assets developed from Ascendis’s Transcon platform. Ascendis, which has an equity stake in Eyconis, granted the biotech rights to develop and commercialize Transcon ophthalmology products globally. —Synnovation Therapeutics, founded and led by veterans of Incyte, launched with $102 million for small molecule drugs addressing validated cancer targets. Lead program SNV1521 is a PARP1 inhibitor that is highly selective to that target and also has the ability to penetrate into the central nervous system. The Wilmington, Delaware-based company is testing this molecule in a Phase 1 clinical trial. Third Rock Ventures led Synnovation’s Series A financing, which included participation from Nextech, Lilly Asia Ventures, Sirona Capital, and Cormorant Asset Management. Photo by Eli Lilly