Hypophosphatasia

Be Bio’s BE-101 works by inserting the human Factor IX (FIX) gene into primary human B cells. Image credit: Shutterstock/ ardhikauw. Be Biopharma has raised $82m in financing to advance a gene therapy targeting hemophilia B to a Phase I/II trial, whilst also adding an ex-Roche exec who was involved with the launch of a haemophilia A treatment to its roster. The financing had big pharma involvement in the form of Bristol Myers Squibb and Takeda Ventures, with venture capital firms ARCH Venture Partners, Atlas Venture, and RA Capital Management participating. Be Bio said the funds, which were also from Alta Partners and the Longwood Fund, will be allocated to the hemophilia B candidate BE-101 and  a newly unveiled programme for hypophosphatasia called BE-102. Alongside the funds, the US biopharma added Suha Patel and Dr. Kiran Patki to its ranks, who will serve as senior vice president of commercial & franchise strategy and senior vice president of clinical development, respectively. Patel was involved in launching the haemophilia A treatment Hemlibra (emicizumab-kxwh) at Roche’s Genentech, whilst Patki previously worked at rare disease biotech Rally Bio. Be Bio’s CEO Dr. Joanne Smith-Farrell said that “some valued colleagues will be moving on” as the company shifts resources toward product development. Be Bio’s BE-101 is a genetically engineered B cell therapeutic that works by inserting the human Factor IX (FIX) gene into primary human B cells, which allows for continuous expression of active FIX levels with a single infusion. Haemophilia B, which affects around 40,000 globally, is an X-linked recessive bleeding disorder caused by a deficiency in clotting factor IX and has traditionally been treated with regular infusions of the protein. The advancement of gene therapies is changing the treatment paradigm for this disorder, with single infusions reducing the burden on patients taking repeated treatments. There are currently two US Food and Drug Administration (FDA)-approved gene therapies for haemophilia B – CSL Behring’s Hemgenix (etranacogene dezaparvovec) and Pfizer’s Beqvez (fidanacogene elaparvovec ). Be Bio’s candidate has an FDA orphan drug designation and fast track status, which confers benefits such as the possibility of seven years of market exclusivity. See Also: TreeFrog and University of Pittsburgh probe TLS role in immuno-oncology Lilly’s Kisunla does not demonstrate “good value” for UK’s NHS The FDA approved an investigational new drug application (IND) in March this year, greenlighting the company to initiate a trial evaluating the gene therapy. The multi-centre, first-in-human dose escalation study (NCT06611436), called BeCoMe-9, will evaluate the safety and preliminary efficacy of intravenously administered BE-101 in adults with moderately severe to severe haemophilia B. The trial is estimated to enrol 24 patients and has a primary endpoint of adverse events and serious adverse events one year post dose. Smith-Farrell said: “We are eager to clinically demonstrate BE-101’s potential to provide a highly durable FIX replacement therapy for Hemophilia B patients. Additionally, we are excited to advance BE-102 to address the needs of a large patient population with few to no therapeutic options.” Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. Thank you. You will receive an email shortly. Please check your inbox to download the Whitepaper. By Cytiva Thematic By downloading this Whitepaper, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

Be Bio’s $82 million round announced Tuesday will help the Cambridge, MA-based biotech fund work for two of its drugs in development, including the first-ever B cell therapy to enter human studies for hemophilia B. While the new round is smaller than its $130 million Series B from 2022, the company plans to use the new funding to reach clinical proof-of-concept for its hemophilia B cell therapy and advance a second candidate for hypophosphatasia, a rare genetic disease that disrupts the development of bones and teeth. CEO Joanne Smith-Farrell told Endpoints News the amount was “what we needed to actually get this program all the way to where we’ve got definitive proof-of-concept.” The startup plans to present clinical data next year for hemophilia B. For hypophosphatasia, it expects to seek an IND in 2026, Smith-Farrell said. Companies developing B cell therapies hope they can essentially be long-term protein factories in the body, but without some of the dangers and side effects that come with other cell and gene therapies. The treatments, if they work, could address a range of diseases where people are missing an essential protein. The $82 million round included investors such as ARCH, Atlas Venture, RA Capital and others. Seattle’s Immusoft in October gave a glimpse at results from the first patient to receive a B cell therapy. Immusoft is developing its treatment for mucopolysaccharidosis type I, a genetic disease in which people are missing an enzyme needed to break down sugars. Be Bio has opened enrollment for a Phase 1/2 study of its hemophilia B therapy, BE-101, to adults with moderate-to-severe disease. The experimental treatment is meant to produce Factor IX, a blood clotting factor, without needing preconditioning. The hope is that the therapy, while durable, will also be redosable if needed.

Bexotegrast at 320 mg was well tolerated up to 40 weeks of treatment with no treatment-related severe or serious adverse events 320 mg cohort demonstrated improvement in liver stiffness by transient elastography at Week 24 compared to placebo Statistically significant improvement in alkaline phosphatase (ALP) levels over 24 weeks compared to placebo Continued improvement in hepatocyte function and bile flow by contrast MRI imaging observed from Week 12 to Week 24 FDA guidance provided clarity on next steps of PSC development program July 15, 2024 -- Pliant Therapeutics, Inc. (Nasdaq: PLRX) today announced positive 24-week data from the 320 mg cohort of INTEGRIS-PSC, a multinational, randomized, double-blind, placebo-controlled Phase 2a clinical trial of bexotegrast in patients with primary sclerosing cholangitis (PSC) and suspected moderate to severe liver fibrosis. The 320 mg treatment group met its primary endpoint of safety, demonstrating that bexotegrast was well tolerated up to 40 weeks of treatment. Pruritus and cholangitis occurred in lower proportions on bexotegrast than on placebo, consistent with previous findings. The trial’s exploratory efficacy endpoints assessed changes in liver stiffness as measured by transient elastography (TE) at 24 weeks, changes in the liver fibrosis markers including Enhanced Liver Fibrosis (ELF) score, as well as liver biochemistry and magnetic resonance imaging (MRI). Bexotegrast at 320 mg demonstrated improvement in liver stiffness compared to placebo at Week 24. A reduction in ELF score was observed at Week 24 in patients at higher risk of disease progression (baseline ELF > 9.8) compared to an increase in ELF on placebo. Stable ELF score was observed from Week 12 to Week 24 in the overall bexotegrast-treated population compared to placebo. Bexotegrast improved markers and symptoms of cholestasis including alkaline phosphatase (ALP), MRI, self-reported itch, and common adverse events associated with PSC. Bexotegrast-treated patients showed decreased ALP levels over 24 weeks, compared to increased ALP on placebo. MRI of the liver demonstrated evidence of further improvement of hepatocyte function and bile flow with bexotegrast at the 320 mg dose from Week 12 to 24. INTEGRIS-PSC was a multinational, randomized, dose-ranging, double-blind, placebo-controlled Phase 2a trial designed to evaluate bexotegrast at once-daily oral doses of 40 mg, 80 mg, 160 mg or placebo up to 12 weeks and 320 mg or placebo for up to 48 weeks in 121 patients with PSC and suspected liver fibrosis. The 320 mg cohort enrolled 27 patients in the active arm and 9 patients in placebo arm. “We could not ask for more from an exploratory Phase 2a study. These longer term INTEGRIS-PSC data continue to highlight bexotegrast’s favorable safety and tolerability profile, further validate its broad antifibrotic activity in diseases of unmet need and suggest the potential for disease stabilization,” said Éric Lefebvre, M.D., Chief Medical Officer of Pliant. “Furthermore, these positive data provide additional confidence in our IPF development program centered on BEACON-IPF, our ongoing global Phase 2b/3 trial.” Bexotegrast 320 mg was Well Tolerated Up to Week 40 with No Drug-Related Severe or Serious Adverse Events The primary endpoint of the INTEGRIS-PSC trial was the evaluation of the safety and tolerability of bexotegrast. Bexotegrast at 320 mg was well tolerated up to 40 weeks of treatment with no treatment-related severe or serious adverse events (SAE). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and consistent with PSC disease symptoms. Bexotegrast 320 mg Continued to Demonstrate Antifibrotic Activity in a PSC Population with Suspected Moderate to Severe Liver Fibrosis at Week 24 The exploratory endpoints of the INTEGRIS-PSC trial included changes in liver stiffness as measured by transient elastography (TE) at 24 weeks, changes in liver fibrosis markers including ELF, liver biochemistry and MRI imaging. These data suggest stabilization of liver fibrosis. Bexotegrast at 320 mg demonstrated a numerical reduction in liver stiffness at Week 24 compared to an increase on placebo, as measured by TE. Liver stiffness is a marker of liver fibrosis that increases over time in patients with PSC. Measurement of liver stiffness by TE can be used to predict the severity and progression of liver fibrosis.1 In patients at high risk for disease progression (baseline ELF ˃ 9.8), bexotegrast-treated patients showed a reduction in ELF score at Week 24 compared to an increase in placebo at Week 24. Across all bexotegrast-treated patients, ELF remained stable on treatment from Week 12 to 24 compared to placebo. Bexotegrast Improved Markers and Symptoms of Cholestasis Bexotegrast-treated patients demonstrated statistically significant reduction in ALP over 24 weeks compared to increased levels on placebo, with greater reductions observed in bexotegrast-treated patients with elevated baseline ALP values. At Week 12, in the MRI sub-study, bexotegrast-treated patients showed increased relative enhancement compared to decreased relative enhancement in the placebo group. At Week 24, bexotegrast-treated patients displayed a further increase in relative enhancement, suggesting continued improvement in hepatocyte function from Week 12 to 24. At Week 12, bexotegrast-treated patients showed decreased time to arrival to the common bile duct compared to placebo, suggesting improved bile flow.2 At Week 24, bexotegrast-treated patients showed faster time to arrival to the common bile duct, suggesting further improvement in bile flow from Week 12 to 24. Interpretation of placebo findings at Week 24 was limited due to the small number of placebo participants (n=˂2) enrolled in the MRI sub-study of the 320 mg cohort. Pruritus and cholangitis are common symptoms of cholestasis in PSC patients.3 Adverse events of pruritus and cholangitis occurred in a lower proportion of bexotegrast-treated patients at 320 mg compared to placebo. Bexotegrast-treated patients demonstrated a stable score on the Itch Numerical Rating Scale relative to a numerical increase on placebo. These findings are consistent with previously reported data from Week 12 across all doses. “I continue to be encouraged by the consistent safety and efficacy trends seen with these data that clearly align with the data previously presented,” said Gideon Hirschfield, FRCP, Ph.D., Lily and Terry Horner Chair in Autoimmune Liver Disease at the University of Toronto and a principal investigator in the INTEGRIS-PSC trial. “These data, alongside those from bexotegrast in IPF, suggest a strong clinical antifibrotic effect across multiple diseases. Today’s PSC data is further strengthened with the new transient elastography data in liver stiffness.” Pliant would like to thank our INTEGRIS-PSC investigators and their study teams for their dedication in support of the successful execution of this trial. Special thanks to the INTEGRIS-PSC clinical trial participants, their families and support networks for helping us advance this promising program. Pliant recently conducted a meeting with U.S. Food and Drug Administration (FDA) to review the potential development path for bexotegrast in PSC. The FDA is supportive of a 52-week, dose-ranging Phase 2b trial employing non-invasive endpoints. Pliant will continue to evaluate the best path forward for this program. PSC is a rare, progressive liver disease of unknown origin, which frequently occurs in the setting of inflammatory bowel disease. PSC affects more than 30,000 patients in the United States and over 100,000 patients worldwide. The disease can occur in all ages, genders, and races. PSC is characterized by inflammation and fibrosis, with progressive liver and biliary damage leading to cirrhosis and liver failure. Currently there are no FDA or EMA-approved therapies for patients with PSC. Therefore, there is a high unmet need for new therapeutic options to address the symptoms and modify the disease progression of this grievous illness. INTEGRIS-PSC was a Phase 2a, multinational randomized, dose-ranging, double-blind, placebo-controlled trial evaluating the safety, tolerability, and pharmacokinetics of bexotegrast administered over 12 weeks in patients with PSC. Patients were enrolled in doses of 40 mg, 80 mg, 160 mg or 320 mg, with a 3:1 randomization ratio (active:placebo) and stratification based on use of ursodeoxycholic acid (UDCA). The primary endpoint was the evaluation of bexotegrast safety and tolerability, and the secondary endpoint is the assessment of pharmacokinetics across the range of doses. Exploratory endpoints measured changes in liver fibrosis markers, ELF and PRO-C3, liver biochemistry and liver imaging. Pliant Therapeutics is a late-stage biopharmaceutical company and leader in the discovery and development of novel therapeutics for the treatment of fibrotic diseases. Pliant's lead product candidate, bexotegrast (PLN-74809), is an oral, small molecule, dual selective inhibitor of αvß6 and αvß1 integrins that is in development in the lead indications for the treatment of idiopathic pulmonary fibrosis, or IPF, and primary sclerosing cholangitis, or PSC. Bexotegrast has received Fast Track Designation and Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) in IPF and PSC and Orphan Drug Designation from the European Medicines Agency in IPF and PSC. Pliant has initiated BEACON-IPF, an adaptive Phase 2b/3 trial of bexotegrast in IPF. Pliant is conducting a Phase 1 study for its third clinical program, PLN-101095, a small molecule, dual-selective inhibitor of αvß8 and αvß1 integrins, that is being developed for the treatment of solid tumors. In addition, Pliant has received regulatory clearance for the conduct of a Phase 1 study of PLN-101325, a monoclonal antibody agonist of integrin α7β1 targeting muscular dystrophies. 1 Corpechot C, et al. Gastroenterology. 2014 Apr;146(4):970-9. 2 Elkilany A, et al. Abdom Radiol (NY). 2021 Mar;46(3):979-991. 3 Karlsen TH, et al. J Hepatol. 2017 Dec;67(6):1298-1323. The content above comes from the network. if any infringement, please contact us to modify.