Genentech’s gantenerumab Fails in Phase III Trial for Alzheimer’s Disease

In yet another setback for an amyloid-targeting drug, Roche’s Genentech division has reported disappointing top-line results from its highly anticipated phase III trial of gantenerumab in early Alzheimer’s disease. The failure is entirely consistent with the overall trend in Alzheimer’s drug evaluations that target amyloid beta – the protein that forms deposits in the brain tissue of patients with the disease – resulting in the abandonment of dozens of candidates.

The GRADUATE I and II studies, which included 1,965 subjects with mild cognitive impairment (MCI) due to Alzheimer’s and mild Alzheimer’s dementia – collectively called early Alzheimer’s – found that gantenerumab had no statistically significant effect on cognitive decline. On the Clinical Dementia Rating-Sum of Boxes (CDR-SB), study participants in GRADUATE 1 and 2 treated with gantenerumab showed a slowing of the clinical decline of -0.31 and -0.19 from baseline score, respectively, which translated to a non-significant 8% and 6% difference with placebo.

Side effects from the antibody were also a potential concern, with 25% of patients receiving gantenerumab experiencing ARIA-E, a type of cerebral edema, though Genentech stated that the vast majority were asymptomatic and “very few” required treatment to be discontinued.

In September, Eisai and Biogen reported top-line results from their lecanemab trial, which showed a strong impact on amyloid clearance, which the companies said was correlated with the drug’s effects on cognition. They reported a 27% reduction in clinical decline on the CDR-SB scale compared to placebo after 18 months, but that data will be scrutinized at the Clinical Trials in Alzheimer’s Disease (CTAD) meeting later this month.

CHMP Recommends’ Dupixent for EU Approval for Prurigo Nodularis

Dupixent, developed by Sanofi and Regeneron, is on track to become the first targeted drug approved in the EU for prurigo nodularis, a rare and severely debilitating skin disease. The European Medicines Agency’s (EMA) human medicines committee (CHMP) has recommended the IL-4 and IL-13 inhibitor Dupixent (dupilumab) for the treatment of adults with moderate to severe prurigo nodularis, a disease that causes hard lumps on the skin that are so itchy that patients scratch themselves to the point of bleeding or pain.

Currently, treatment typically consists of oral or topical corticosteroids, antihistamines, and some antidepressant drugs, but responses are frequently inadequate, vary greatly between patients, and carry a high risk of side effects if used long-term.

The CHMP gave the drug a positive opinion at its monthly meeting last week, based on the findings of two phase III studies – PRIME and PRIME2 – which showed that Dupixent was significantly better than placebo at reducing itch and skin lesions in adult prurigo nodularis patients who were unable to control symptoms with other medications. Dupixent treatment resulted in clear or nearly clear skin in nearly half (45%) of patients after 24 weeks of treatment, compared to 16% of control subjects.

The decision paves the way for the European Commission to approve Dupixent in this indication in the coming weeks, potentially making tens of thousands of additional patients eligible for treatment with the drug.

In September, the US FDA approved Dupixent for adults with prurigo nodularis, making it an option for an estimated 75,000 patients with the condition and adding to the drug’s previous approvals for atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic oesophagitis. Dupixent sales increased by 45% to around USD 2.4 billion in the third quarter, driven by demand in its main atopic dermatitis and severe asthma indications, which were boosted by approvals in younger age groups, as well as smaller add-on uses. According to Sanofi and Regeneron, Dupixent could earn around USD 13 billion per year at its peak, propelling the drug into the top five pharmaceutical sellers.

NRG Announces £16 Million Series A for IND for Parkinson’s and ALS

NRG Therapeutics an innovative neuroscience company targeting mitochondrial dysfunction, announced closing a £16 million Series A financing, directed by Omega Funds and joined by additional new investor Brandon Capital and founding investor the Parkinson’s Virtual Biotech. In connection with the funding, Omega Funds Managing Director Claudio Nessi, Partner Francesco Draetta, and Brandon Capital Partner Jonathan Tobin have joined the company’s Board of Directors

In order to develop disease-modifying therapeutics to reduce or stop the progression of neurodegenerative diseases including Parkinson’s disease and Amyotrophic Lateral Sclerosis, NRG is using advancements in mitochondrial biology. The Series A proceeds will advance the company’s potential first-in-class brain-penetrant small molecules via IND-enabling studies

Small molecules with a new mechanism of action that inhibit the mitochondrial permeability transition pore are part of the company’s pre-clinical pipeline. Since mitochondria are the cells’ “powerhouses” or “batteries,” they are crucial for preserving cell health. There is a substantial body of evidence showing that mitochondrial dysfunction is common in many degenerative diseases. Inhibition of the mPTP has been shown to protect neurons, reduce neuro-inflammation, and expand survival in pre-clinical disease models.

According to in vitro research, NRG’s investigational novel drugs have the potential to stop or significantly slow the progression of Parkinson’s or amyotrophic lateral sclerosis in patients by protecting mitochondria and boosting the survival of human cells. NRG’s medicines would be the first disease-modifying treatment to stop Parkinson’s disease development for patients if clinical studies are successful, as present medications simply manage disease symptoms.

By activating the innate immune sensor STING, the protein TDP-43 causes neuroinflammation in ALS, according to a novel pathogenic mechanism discovered by Professor Seth Masters at Australia’s WEHI.

Parkinson’s Virtual Biotech is the international drug discovery and development program established in 2017 by Parkinson’s U.K., the largest European charitable funder of Parkinson’s research. Since 2019, Virtual Biotech has backed NRG’s work as it looks to advance new treatments for Parkinson’s in years and not decades.

Parkinson’s affects approximately 10 million individuals worldwide due to the loss of specific dopamine-producing cells in the brain that controls muscle movement. It is the fastest-growing neurological disorder globally, presenting a significant healthcare challenge for society. Amyotrophic lateral sclerosis is a rare fatal neurodegenerative disorder that leads to death within 3 to 5 years of diagnosis. The marketed disease-modifying treatments for amyotrophic lateral sclerosis extend survival by approximately 3 to 6 months. Given this extension in life is modest and patients are highly weakening in the terminal phase of the disease, an improved disease-modifying medicine is desperately needed.

FDA Backs AstraZeneca’s PT027 for Severe Asthma in Adults

AstraZeneca has taken a step towards winning approval of its asthma rescue medication PT027 in adults after the FDA advisory committee voted strongly that its benefits outweigh the risks. But the panel delivered a split decision on adolescent use and voted against approval in children. 

PT027 is a fixed-dose combination of albuterol and budesonide, breezed through part of the meeting as the panelists voted 16 to one that the data support a favorable benefit-risk assessment of the use of the drug as a rescue medication in adults. The panelists noted the strong efficiency data and lack of safety signals. 

AstraZeneca had a rougher ride when the experts discussed the data it presented on two pediatric populations: children aged 4 to 11 years and adolescents aged 12 to 18. Doubts about the benefit-risk profile in children and adolescents rest on the validity of extrapolating the results from a phase 3 trial to the younger patients. The trial, MANDALA, enrolled adults and adolescents. 

Alex Kaizer, Ph.D., assistant professor at the University of Colorado Anschutz Medical Campus, raised concerns about the data heterogeneity that made it “challenging to be highly confident that we could extrapolate these results.” Bridgette Jones, M.D., professor of pediatrics at Children’s Mercy Kansas City, was more optimistic, arguing that “full extrapolation is appropriate in this age group, and that you would expect similar outcomes for favorable risk benefit as in adults.“

That mix of views resulted in a 9-8 vote against the candidate in adolescents aged 12 to 18. The panel was more united on whether the benefits outweigh the risks of the treatment in children aged 4 to 11 years, with the experts voting 16 to one against the candidate in the age group. Jones, the sole yes vote, said some children might benefit, and it is up to doctors to identify them.

FDA Clears Imfinzi and Imjudo with chemotherapy for NSCLC

On 11 November 2022, AstraZeneca announced that the US FDA had approved Imfinzi (durvalumab) in combination with Imjudo (tremelimumab) plus platinum-based chemotherapy has been approved in the US for the treatment of adult patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on POSEIDON Phase III trial results, in which the therapy showed significant survival benefits with a limited course of Imjudo added to Imfinzi and chemotherapy. 

AstraZeneca’s POSEIDON trial was a randomized, open-label, multicenter, global, Phase III trial of Imfinzi plus platinum-based chemotherapy, or Imfinzi, Imjudo, and chemotherapy, versus chemotherapy alone in the 1st-line treatment in patients with metastatic NSCLC. The trials were conducted in 18 countries and more than 150 centers. Primary endpoints included progression-free survival (PFS) and OS for the Imfinzi plus chemotherapy arm. Key secondary endpoints included PFS and OS in the Imfinzi plus Imjudo and chemotherapy arm. As both PFS endpoints were met for Imfinzi plus chemotherapy and Imfinzi, Imjudo, and chemotherapy, the prespecified statistical analysis plan allowed for testing OS in the Imfinzi plus Imjudo and chemotherapy arm. This treatment combination demonstrated a reduced risk of disease progression or death by 28% compared to chemotherapy alone.

In the United States, NSCLC poses a serious health burden, and it is the second most commonly diagnosed cancer in the countyr. As per DelveInsight, in 2020, about 227,800+ incident cases of lung cancer were observed in the United States, of which ~85%, i.e., 193,600+, were NSCLC cancer patients. In 2022 more than 236,000 patients are expected to be diagnosed. Moreover, the prognosis is particularly poor for patients with metastatic NSCLC, as only approximately 8% will live beyond five years after diagnosis. The approval of Imfinzi and Imjudo with chemotherapy is expected to immensely improve the non-small cell lung cancer  treatment market dynamics in the coming years. 

NICE Recommends Ipsen’s Cabometyx (cabozantinib) for Hepatocellular Carcinoma  

National Institute for Health and Care Excellence (NICE) recommends Ipsen’s Cabometyx (cabozantinib) for treating advanced hepatocellular carcinoma (HCC) in England and Wales. 

Hepatocellular carcinoma is the most common type of primary liver cancer. The indication is mostly seen in people with chronic liver diseases, majorly cirrhosis caused by hepatitis B or hepatitis C infection. Cabozantinib is an oral tyrosine kinase inhibitor, majorly vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL. The drug is administered daily, along with outpatient monitoring. Based on the results of the CELESTIAL Phase III pivotal trial, the drug showed significant improvement in progression-free survival (PFS) and overall survival (OS). The trial was conducted on 707 participants, each receiving a daily dose of 60 mg cabozantinib. 

The comparison showed considerable results as compared to the placebo, as the overall population was 10.2 months with cabozantinib and 8.0 months with placebo. The facility ratio of people in England dying after being diagnosed with lung cancer is 13%. 

Director of communications & policy at the British Liver Trust, Vanessa Hebditch, said: “People living with HCC have a poor prognosis and there are very few treatments available. Often, the disease is diagnosed so late that palliative care is the only option.”

Hebditch continued: “Treatments that buy extra time can not only positively impact those individuals, but can also have a huge positive impact on families and the wider community.”

Professor Tim Meyer, professor of experimental cancer medicine at UCL Cancer Institute and honorary consultant in medical oncology at the Royal Free Hospital, said: “HCC is the third leading cause of cancer death worldwide and has one of the lowest five-year survivals of all cancers recommendation by NICE will make cabozantinib available to such patients and provides an important addition to the therapeutic landscape for HCC.”

NICE Backs Use of Merck’s KEYTRUDA for TNBC

The patients of triple-negative breast cancer (TNBC) in England will now be able to access immunotherapy at the early stages of their treatment. This happened after the National Institute for Health and Care Excellence (NICE) recommended using Merck & Co/MSD’s KEYTRUDA (pembrolizumab) to treat high-risk early-stage or locally advanced TBNC. 

This came after the results from the placebo-controlled KEYNOTE-522 trial were conducted to evaluate the efficacy of pembrolizumab. The trial was conducted among 1,174 patients with newly diagnosed, previously untreated, and non-metastatic TNBC.

As per the results, the drug pembrolizumab satisfied the primary endpoints of event-free survival and pathological complete response. After a median period of 39.1 months, KEYTRUDA, in combination with chemotherapy, showed significant improvements in EFS as compared to chemotherapy alone. 

Triple-negative breast cancer (TNBC) is a type of breast carcinoma that lacks any of the receptors that a normal breast carcinoma carries. It accounts for almost 10-15% of total breast carcinoma. Cancer mainly does not have the female hormone estrogen and progesterone. They also do not produce the human epidermal growth factor (HER2) protein. 

“TNBC is an aggressive type of breast cancer that disproportionately impacts black people and those under 40. Previously, there was no immunotherapy treatment option available for people with early stage or locally advanced TNBC, creating an unmet need for these patients,” said David Long, head of oncology at MSD UK. “I am delighted by NICE’s decision to make the first immunotherapy for early stage TNBC available. This decision will hopefully enable patients to have a more positive treatment outcome. MSD is proud to lead the way for this under-served patient population.”