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‘Tooth regrowth’ drug, if successful, can aid people to grow a new set of teeth who lack them due to a congenital condition called Anodontia

In a breakthrough, a team of Japanese scientists has developed a drug that can regenerate lost teeth in adults, an advance that is now moving towards human clinical trials.

Scientists at Kyoto University and the University of Fukui focused on a protein called USAG-1, which, synthesised by a gene, was found to limit the growth of teeth. The antibody targeting USAG-1 could stimulate tooth growth in mice suffering from tooth agenesis, a congenital condition 

Describing in a paper, published in the journal Science Advances, they said the ‘tooth regrowth’ drug, if successful, can aid people to grow a new set of teeth who lack them due to a congenital condition called Anodontia.

It causes the growth of fewer than a full set of teeth, present in around 1 per cent of the population. 

According to Japan’s national daily news site, the Mainichi, the scientists will begin clinical trials in July 2024 and expect to roll out for general use in 2030.

The study is the first to show the benefits of monoclonal antibodies on tooth regeneration and provides a new therapeutic framework for a clinical problem that can currently only be resolved with implants and other artificial measures.

“We knew that suppressing USAG-1 benefits tooth growth. What we did not know was whether it would be enough,” said Katsu Takahashi, one of the lead authors of the study and a senior lecturer at the Kyoto. 

Takahashi explained the fundamental molecules responsible for tooth development have already been identified.

“The morphogenesis of individual teeth depends on the interactions of several molecules including BMP, or bone morphogenetic protein, and Wnt signalling,” he noted.

Guessing that targeting the factors that antagonise BMP and Wnt specifically in tooth development could be safer, the team considered the gene USAG-1. 

The scientists therefore investigated the effects of several monoclonal antibodies for USAG-1. Monoclonal antibodies are commonly used to treat cancers, arthritis, and vaccine development.

USAG-1 interacts with both BMP and Wnt. As a result, several of the antibodies led to poor birth and survival rates of the mice, affirming the importance of both BMP and Wnt on whole body growth. One promising antibody, however, disrupted the interaction of USAG-1 with BMP only.

Experiments with this antibody revealed that BMP signalling is essential for determining the number of teeth in mice. Moreover, a single administration was enough to generate a whole tooth. Subsequent experiments showed the same benefits in ferrets, animals with similar dental patterns to humans. “Conventional tissue engineering is not suitable for tooth regeneration. Our study shows that cell-free molecular therapy is effective for a wide range of congenital tooth agenesis,” said Manabu Sugai of the University of Fukui, a co-author of the study.

Insilico Medicine’s novel AI-generated small molecule inhibitor drug represents a new milestone in pharmaceutical drug development.

The world’s first AI-generated anti-fibrotic small molecule inhibitor drug has been administered to the first human patients. Phase II clinical trials in the US and China are now underway for INS018_055, Insilico Medicine’s potentially first-in-class oral drug candidate.

Achievement of the first dose in human patients is a “milestone” for AI-driven drug discovery and drug development, stated Feng Ren, PhD, co-CEO and Chief Scientific Officer of Insilico Medicine.

Initiating Phase II trials for an AI-generated drug

The Phase II study will assess the safety, tolerability, pharmacokinetics and preliminary efficacy of 12-week oral INS018_055 dosage in subjects with the rare lung disease idiopathic pulmonary fibrosis (IPF). Patients will be divided into four parallel cohorts. To further evaluate the drug candidate in wider populations, the company plans to recruit 60 subjects with IPF at about 40 sites in both the US and China. 

In early 2023, INS018_055 received positive topline data in Phase I. The small molecule inhibitor was dosed in 78 and 48 healthy subjects, divided into cohorts focusing on a single ascending dose (SAD) study and multiple ascending dose (MAD) study.

The international multi-sites Phase I studies demonstrated consistent results, indicating favourable safety, tolerability of the AI-generated INS018_055. The observed human PK of INS018_055 showed no significant accumulation after seven days and exhibited a favourable PK profile. INS018_055 was generally safe and well tolerated by healthy volunteers in the study. This data supported the initiation of the Phase II study.

“With demonstrated potential against both fibrosis and inflammation, INS018_055 could offer another option for patients worldwide,” commented Ren.

The company first described the concept of using generative artificial intelligence for the design of novel molecules in a peer-reviewed journal in 2016.

In February 2021, the small molecule drug INS018_055 started a first-in-human study for IPF in November 2021. The US Food and Drug Administration (FDA) granted Orphan Drug Designation to INS018_055 for the treatment of IPF in February 2023.

On 1st July, Australia became the first country to allow psychiatrists to prescribe MDMA, also known as ecstasy, for PTSD. Psilocybin, the psychoactive ingredient in hallucinogenic (or ‘magic’) mushrooms, can also be given to those with treatment resistant depression (TRD).

The two drugs have now been placed on the list of approved medicines by the Therapeutic Goods Administration (TGA), after a near-three-year process and extensive consultation with experts. Both drugs have also shown potential for treatment of anxiety, anorexia, and substance addiction.

While Canada and Israel permit individual use of the drugs on compassionate grounds or in clinical trials, Australia has now become the first country to regulate the drugs as medication, which are to be prescribed by approved psychiatrists.

The intention for this legalisation was announced in February this year and, whilst shocking for some, has been welcomed by others. Chris Langmead, deputy director of the Neuromedicines Discovery Centre at the Monash Institute of Pharmaceutical Sciences, commented that there had previously “been very few advances in the treatment of persistent mental health issues in the last 50 years”.

It’s not just in Oceania that such open-minded developments have been taking place: Oregon was the first US state to legalise adult use of psilocybin and the drug was decriminalised in Colorado last year. Indeed, the US Food and Drug Administration (FDA) deemed psilocybin a “breakthrough therapy” back in 2018.

Furthermore, only late last month the FDA released draft guidance on the design of clinical trials for testing psychedelic drugs as potential treatments for a wide range of medical conditions.

Without final FDA determination, however, the American Psychiatric Association has not yet given its endorsement, and it is generally agreed – both in the US and Australia – that more research on efficacy and safety is needed, psychedelics known to cause hallucinations. The FDA’s director of psychiatry, Tiffany Farchione, stated that “[t]hese are still investigational products.”

A phase II trial by Compass Pathways, published late last year in the New England Journal of Medicine, showed that a 25 mg dose of psilocybin was twice as effective as a 1 mg dose in combating TRD – but significant side effects were noted.

Dr Paul Liknaitzky, head of Monash University’s Clinical Psychedelic Lab, said: “There are concerns that evidence remains inadequate and moving to clinical service is premature [and] that incompetent or poorly-equipped clinicians could flood the space […]”

Another concern is that treatment will be unaffordable for most: in Australia, the drugs are to be priced at about AUS$10,000 (roughly £5,200) per patient for treatment.

As Beckley Psytech’s Cosmo Feilding Mellen wrote for pharmaphorum recently, according to the World Health Organization (WHO), of the 280 million people globally that have depression, a third live with TRD, where a person’s depression symptoms do not improve with first and second-line treatment.

UK-company Beckley Psytech has initiated a phase IIa trial in its synthetic 5-MeO-DMT (or Mebufotenin) candidate, BPL-003, as a treatment for TRD, exploring the safety, efficacy, and pharmacokinetics of a single dose of BPL-003, in combination with psychological support.

Psilocybin, a psychedelic compound found in certain mushrooms, could offer a more cost-effective treatment option for major depressive disorder than current methods, according to research from Clerkenwell Health and the University of Greenwich.

Findings from the study, titled ‘Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model‘, indicate that combining psilocybin with therapy could be more cost-effective compared to current methods used in the treatment of major depression, such as cognitive behavioural therapy (CBT). The cost of psilocybin-based treatment, priced at £1,200, combined with therapy from a single therapist, was estimated to be £5,239. Comparatively, researchers note costs of £3,528 for conventional medication alone, £4,250 for CBT alone, and £4,197 for a combination of the two.

The study was authored by leading experts in the economics and psychedelics field, including Professor Paul McCrone from the University of Greenwich, neuro-psychopharmacologist David Nutt, and researchers Henry Fisher and Clare Knight from Clerkenwell Health, a start-up commercial clinical research organisation specialising in psychedelic treatments.

Professor McCrone said: “While this is a relatively expensive treatment option, the improved outcomes that seem to be achieved may justify this extra cost, especially as there are few treatment options for those with the hardest-to-treat forms of depression. More research is needed, especially on the level of therapist support that is required, but this is an interesting therapy and could well be positioned alongside more conventional treatments.”

In addition to the cost-effectiveness, researchers also identified that patients who received psilocybin-based treatment experienced a higher quality of life after treatment, with quality-adjusted life years (QALYs) nearly 10% greater than those treated with CBT – the next most effective treatment option.

This announcement comes just days after Australia ushered in a new era of treatment, becoming the first country in the world to legalise the use of psilocybin (and MDMA) to treat psychiatric conditions, including depression and post-traumatic stress disorder. While psilocybin cannot be lawfully possessed or prescribed in the UK, there has been much debate over whether the substance should be legalised.

In the UK, the subject of mental health treatment has been put under the spotlight in recent months. Last month, a BBC investigation uncovered data showing that more than a quarter of antidepressant users in England, approximately two million individuals, have been taking the medication for five years or more. With the number of people prescribed antidepressants rising, the cost of treating depression is significant, with one study from the London School of Economics estimating that depression costs the UK economy at least £118 billion a year.

Dr Henry Fisher, chief scientific officer at Clerkenwell Health, said: “With rising numbers of people in the UK prescribed antidepressants and increasing chronic use, it’s clear the need for innovative treatments for depression has never been more pressing. Our research finds that there is great potential for psilocybin to be a cost-effective therapy for severe depression – with higher quality impacts for the individuals and society.

“We’re calling on health professionals and policymakers to seriously consider these findings, which suggest psilocybin could be genuinely ground-breaking for the NHS and for the millions of people being treated for depression in the UK.”

While study results show that psilocybin has the potential to be a cost-effective therapy for severe depression, researchers note that this outcome is dependent on the level of psychological support that is provided to patients receiving psilocybin and the price of the drug itself. Moreover, further data on long-term outcomes will be required to improve the evidence base.

Clerkenwell Health is now working on designing and delivering several trials around testing the use of psychedelics such as psilocybin to treat conditions, including depression and PTSD, and is actively recruiting patients.

Astellas Pharma Inc has announced that the US Food and Drug Administration (FDA) has accepted and granted Priority Review of its zolbetuximab Biologics License Application (BLA). If approved, the first-in-class investigational Claudin 18.2 (CLDN18.2)-targeted monoclonal antibody would be the first CLDN18.2-targeted therapy available in the US for patients with advanced gastric and gastroesophageal cancers.

Gastric cancer, more commonly known as stomach cancer, is the fifth most diagnosed cancer in the world. In the US alone, roughly 26,500 people will be diagnosed with gastric cancer and 11,130 will die from the disease in 2023. Frequently, early-stage gastric cancer symptoms overlap with more common stomach-related conditions. This often results in gastric cancer diagnosis occurring in the advanced or metastatic stage, or once it has spread from the tumour origin to other body tissues or organs.

The five-year survival rate for patients at the metastatic stage is 6.6%.

Zolbetuximab is intended for first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumours are CLDN18.2-positive. Zolbetuximab acts by binding to CLDN18.2 on the cancer cell surface of gastric epithelial cells. In pre-clinical studies, this binding interaction then induces cancer cell death by activating two distinct immune system pathways — antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

The BLA is based on results from the phase 3 SPOTLIGHT and GLOW clinical trials. The SPOTLIGHT study evaluated zolbetuximab plus mFOLFOX6 – a combination regimen that includes oxaliplatin, leucovorin, and fluorouracil – compared to placebo plus mFOLFOX6.

The GLOW study evaluated zolbetuximab plus CAPOX – a combination chemotherapy regimen that includes capecitabine and oxaliplatin – compared to placebo plus CAPOX.

In both studies, approximately 38% of patients screened for the trials had tumours that were CLDN18.2-positive, as determined by a validated immunohistochemistry assay.

The FDA reviewed the application under its Real-Time Oncology Review (RTOR) programme, which aims to explore a more efficient review process to ensure that safe and effective treatments are made available to patients as early as possible.

Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target action date of 12th January 2024 and Astellas has already reflected the impact of this acceptance in its financial forecast of the current fiscal year ending 31st March 2024.

Moitreyee Chatterjee-Kishore, senior vice president and head of immuno-oncology development at Astella, said: “Astellas is committed to bringing innovative therapies to patients with hard-to-treat cancers, including gastric cancer […] The FDA’s acceptance of the Biologics License Application filing and Priority Review designation for zolbetuximab confirms the urgent therapeutic need and brings us one step closer to delivering on this commitment to patients, families, and caregivers.”

At ASCO 2023, pharmaphorum editor-in-chief Jonah Comstock spoke with Mark Reisenauer, president of US commercial at Astellas. Reisenauer gave an update on some of Astellas’s abstracts at the show, including the trials in gastric cancer, bladder cancer, and head and neck cancer. Watch the video here or below.

Kicking off this year’s American Academy of Neurology annual meeting on Friday morning, AbbVie shared more positive results for its migraine drug, Qulipta (atogepant).

Originally approved in 2021 for the preventative treatment of episodic migraine headaches, AbbVie has continued to add indications for its CGRP receptor antagonist. On Tuesday, AbbVie won approval from the FDA to expand the drug’s label further to include chronic migraine.

New results from another Phase III trial studying the drug demonstrated its efficacy for treating episodic migraine in patients for which two to four classes of conventional medications have failed.

In the ELEVATE study, Qulipta decreased patients’ mean monthly migraine days by 4.2 days, a significant reduction to the 1.85 days seen in the placebo arm over the 12-week treatment period.

CGRP receptor antagonists are the first class of migraine drugs that show similar efficacy to triptans, without vasoconstrictive activity and with fewer side effects. Triptans should not be used by patients with a history or risk factors for heart disease, high blood pressure and other common health conditions, making drugs like Qulipta an important option.

AbbVie’s drug is now the only oral CGRP receptor antagonist approved as a preventive treatment for both episodic and chronic migraine frequencies. The once-daily oral medication has only been approved in the U.S. at this point.

AbbVie has three treatments available for migraine in its neuroscience portfolio – its second-highest earner after its immunology drugs. Botox Therapeutic, Ubrelvy and Qulipta collectively brought in revenues of over $3 billion in the U.S. in 2022.

The migraine drug market is massive, affecting over 1 billion people worldwide every year. It’s one of the highest causes of disability in adults under 50.

Last spring, Pfizer made a play into the migraine market when it dropped $11.6 billion to acquire Biohaven. Its bet paid off in March, when the FDA approved its nasal spray Zavzpret (zavegepant) for the acute treatment of migraine in adults.

Zavzpret is the first CGRP antagonist nasal spray on the market for migraines, having demonstrated significantly higher rates of pain relief, durability and return to normal function compared to placebo. An oral formulation of the drug is in Phase II for migraine prevention, a market where it could contend with AbbVie’s Qulipta.

A first-line B-cell lymphoma treatment shown to reduce the risk of disease progression or relapse by 27 percent has been approved by the FDA.

The US Food and Drug Administration (FDA) has approved Polivy^® (polatuzumab vedotin-piiq) in combination with Rituxan^® (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP). “It has been nearly 20 years since a new treatment option has become available to people newly diagnosed with diffuse large B-cell lymphoma,” shared Dr Levi Garraway, PhD, Chief Medical Officer and Head of Global Product Development at Roche.

The combination treatment is indicated for adults who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index (IPI) score of two or greater.

The FDA’s approval

The US regulatory body’s approval is based on pivotal data from POLARIX, an international Phase III trial of 879 patients. It demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to R-CHOP. The risk of disease progression, relapse or death was reduced by 27 percent with Polivy plus R-CHP compared with R-CHOP.

The decision switches the accelerated approval of Polivy in combination with bendamustine and Rituxan for relapsed or refractory (R/R) DLBCL after at least two prior therapies, to regular approval.

Polivy for diffuse large B-cell lymphoma

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC), stated Roche. The ADC binds to cancer cells such as CD79b and destroys these B cells through the delivery of an anti-cancer agent, which is thought to minimise the effects on normal cells. The CD79b protein is expressed in the majority of B cells. This is an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL).

Polivy is being developed by Genentech, part of the Roche Group, using Seagen ADC technology.

DLBCL is the most common form of non-Hodgkin’s lymphoma in the US. Around 31,000 people in the US are predicted to be diagnosed with the disease in 2023.

While many patients are responsive to initial treatment, as many as four in 10 people with DLBCL do not respond or relapse. Standard of care for DLBCL is Rituxan plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). For those who have initial treatment, most relapses occur within two years of starting treatment. The majority of those who require subsequent lines of therapy have poor outcomes.

Over 70 countries have approved this Polivy combination in adults with previously untreated DLBCL, including in the EU, UK, Japan, Canada and China. The treatment is approved in more than 80 countries worldwide for adults with relapsed or refractory (R/R) DLBCL after one or more prior therapies.

Vertex Pharma and CRISPR Therapeutics have become the first companies to file for FDA approval of a therapy based on gene-editing technology.

The two partners have submitted a marketing application exagamglogene autotemcel (exa-cel, formerly CTX001) for blood disorders sickle cell disease (SCD) and beta thalassaemia, just 10 years after the Nobel Prize-winning CRISPR/Cas9 gene-editing technology first emerged from the lab, and seven years after the first CRISPR therapy started clinical testing.

Vertex and CRISPR started preparing the FDA application last November, and have asked for a priority review from the FDA to try to reduce the review time at the agency down to eight months from submission, rather than 12 months.

Exa-cel is a little further down the regulatory route in Europe, where regulators in the EU and UK have already validated filings and started the clock ticking on their reviews.

The therapy is an ‘ex vivo’ application of gene-editing, in which the technology is used as a one-shot therapy to modify a patient’s own cells outside the body to make foetal haemoglobin (HbF), which can serve as a substitute to regular haemoglobin in both SCD and beta thalassaemia.

Reverting to HbF in thalassaemia and SCD patients produces normal, healthy red blood cells, rather than the misshapen cells produced by faulty haemoglobin in the two disorders. The elevation of HbF is designed to reduce or eliminate painful and debilitating vaso-occlusive crises (VOCs) in SCD, as well as the need for blood transfusions in patients with TDT.

“Within a decade, we have progressed from the discovery of the CRISPR platform to the first regulatory filings for a CRISPR-based therapy, which speaks to the transformative nature of CRISPR technology,” commented Phuong Khanh Morrow, chief medical officer at CRISPR.

The completion of the rolling biologics license application (BLA) for exa-cel means Vertex and CRISPR have passed the historic milestone ahead of bluebird bio, which has seen delays in in its plan to file its competing gene-editing therapy for SCD – lovotibeglogene autotemcel (lovo-cel) – in the first quarter of this year.

bluebird has the accolade for bringing the first gene therapy for thalassaemia to market, however, having won FDA approval for its Zynteglo (betibeglogene autotemcel or beti-cel) in transfusion-dependent thalassaemia (TDT) last year. Like all one-shot, gene-directed therapies, Zynteglo has been launched at a high price – $2.8 million.

Vertex has estimated there are around 32,000 patients in the US who could be eligible for treatment with exa-cel if approved, but hasn’t yet commented on its pricing plans for the therapy, or provided any sales projections.

Novo Nordisk has put $75 million down on the table to partner Canadian biotech Aspect Biosystems’ cell-based therapies for diabetes and obesity.

The upfront payment is backed by up to $650 million in milestones for each product that arises from the collaboration, and with four projects in mind the total value of the deal could reach more than $2.6 billion. Novo Nordisk has licensed exclusive worldwide rights to the four projects.

Aspect’s business has been founded on a 3D bioprinting technology that it uses to create implantable tissues that can replace damaged organ functions; for example, the insulin-producing beta cells in the pancreas that are destroyed in type 1 diabetes.

That is the first target of the alliance with Novo Nordisk, which makes sense, given the Danish drugmaker’s strong heritage in diabetes with its insulin and GLP-1 agonist products. Type 2 diabetes and obesity projects will follow, according to the partners.

Novo Nordisk has been actively investigating the development of a so-called ‘artificial pancreas’ for diabetes for many years and, according to Aspect, will bring expertise in engineering stem cells to differentiate into a wide variety of cell types, including beta cells. It also has the ability to produce those cells at the scale needed for clinical testing and commercialisation.

Aspect’s contribution stems from its ability to construct those engineered cells into structures that are “biologically functional, encapsulated to be immune-protective, and suitable for surgical implantation,” said the partners.

At the moment, most attempts to create an artificial pancreas rely on hardware technologies – continuous glucose monitors (CGM) implanted under the skin and wearable insulin pumps – which can vary the delivery of insulin dependent on the needs of the patient.

While a big step forwards for patients, the prospect of a biological replacement pancreas that works in the body without any need for power and insulin reservoirs and pumps remains a holy grail for the treatment of diabetes.

Some therapies using stem cells harvested from umbilical cord tissue have shown promise in early clinical testing – for example, differentiated into beta cells in the body that produce insulin and appear to improve blood glucose control – but the work remains highly experimental.

One key hurdle has been protecting the implanted cells from attack by the immune system unless they are sourced from a matched donor, which Aspect professes to have solved using its technology platform.

Other companies working in this area include Vertex Pharma, which recently secured FDA approval to start trials of its encapsulated cell therapy for type 1 diabetes, called VX-264.