Target $16
Monday, February 27, 2023
Reata, Friedreich’s Ataxia Patients Await Potential First Approval
There are currently no disease-modifying treatments for Friedreich’s ataxia (FA), a rare, degenerative neuromuscular disorder. That could change on Feb. 28, as the FDA is expected to make a decision about Reata Pharmaceuticals’ omaveloxolone.
Touted as one of the top potential neurodegenerative approvals to watch in 2023, omaveloxolone activates Nrf2, a transcription factor that helps resolve inflammation by restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signaling.
In a registrational trial of 103 patients, a group of physicians and Reata representatives writing in the Annals of Neurology said omaveloxolone “significantly improved neurological function compared to placebo and was generally safe and well tolerated.”
Named after the German physician Nikolaus Friedreich, who first discovered it in the 1860s, Friedreich’s ataxia affects approximately 5,000 people in the U.S.
It is caused by a trinucleotide repeat expansion in the first intron of the frataxin (FXN) gene, which encodes the mitochondrial protein frataxin. This expansion leads to reduced frataxin expression, resulting in mitochondrial iron overload and uncoordinated muscle movement (ataxia).
FA typically begins in childhood, with most patients succumbing to the disease by their mid-30s, often from cardiovascular problems.
While Reata is up first with the FDA, several other companies are vying to be next.
PTC Therapeutics: Q2 Readout
PTC Therapeutics is expecting data from the Phase II/III MOVE-FA trial in the second quarter of 2023.
MOVE-FA is assessing vatiquinone, an experimental small molecule that inhibits 15-Lipoxygenase, a primary regulator of the oxidative stress and inflammation response pathways.
A key part of FA disease pathology, oxidative stress leads to chronic neural inflammation, where the inflammatory response can’t be turned off.
“When things go wrong with mitochondria, that can lead to disease states like FA,” Stuart Peltz, Ph.D., CEO, told BioSpace.
Adenosine triphosphate (ATP), the body’s primary energy source, is made in the mitochondria using an electron transfer chain. But these electrons need to be carefully regulated. If released from the mitochondria, they can interact with proteins and DNA and can cause loss of activity, Peltz said.
The 15-Lipoxygenase enzyme plays a key role in regulating neuroinflammation.
“If the 15- Lipoxygenase pathway is activated as a consequence of dysregulation of the mitochondrial electron transfer pathway, then you’ve got a problem,” Peltz said. “The inflammatory system is chronically on and instead of protecting the body, you have this inflammatory milieu that starts to cause damage.”
In a previous Phase II trial, vatiquinone demonstrated what the company called “a statistically significant effect” at the 24-month mark. It also had a “favorable” safety profile in more than 500 patients.
Patients typically lose about two points per year on the modified Friedreich’s Ataxia Rating Scale (mFARS), which measures disease progression, Peltz said. “If you can stabilize the patient, you're doing a good thing.”
Targeting the Root Cause
Pennsylvania-based Larimar Therapeutics expects topline data from a Phase II trial of CTI-1601 during the second half of 2023. The company’s sole clinical-stage product, CTI-1601, is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of FA patients.
In healthy people, a small protein sequence attached to frataxin carries the frataxin molecule across the mitochondrial membrane. It is cut off by an enzyme once in the mitochondria.
“[CTI-1601 has a cell-penetrating peptide attached to the frataxin molecule. The cell-penetrating peptide is a short sequence that's intended to get the molecule across the cell membrane and across the mitochondrial membrane,” Carole Ben-Maimon, M.D., president and CEO, told BioSpace.
It also contains a cleavage site that enables the cell-penetrating sequence and mitochondrial targeting sequence to be removed so the frataxin stays where it’s supposed to.
When the Phase II data reads out, Larimar will be looking for safety pharmacokinetics and changes in frataxin levels. Ben-Maimon hopes to repeat Phase I data that showed daily injections of CT1-1601 given at 50 mg or 100 mg led to increased levels of frataxin in buccal cells in the skin, which are correlated to FA disease burden.
She said CTI-1601’s differentiator is that it gets at the root cause of the disease, replacing the frataxin of which FA patients don’t make enough.
Conversely, Reata’s omaveloxolone activates Nrf2, which stimulates the production of certain proteins. Therefore, the drug works as an antioxidant, she said.
While omaveloxolone will not be curative, “I think the different mechanisms could potentially be synergistic. I don't think it's one or the other.”
Regulatory Precedent
PTC and Larimar are both following the upcoming Reata decision closely.
While Peltz would not comment directly on omaveloxolone’s chances of approval, he said it would be interesting to see the point of view taken by the FDA’s neurology division.
Ben-Maimon agreed that it is a precedent-setting decision.
‘If omaveloxolone is approved, that will set the gold standard from the standpoint of what FDA is willing to accept or not accept,” she said.
To date, the expectation has been a double-blind, placebo-controlled trial, and Larimar expects to have to do the same. Though, Ben-Maimon added that her company might be able to use frataxin levels as a surrogate endpoint in addition to clinical outcomes.
Reata’s NDA for omaveloxolone was granted priority review in May 2022. The PDUFA date was later extended until Feb. 28, 2023, to allow the FDA additional time to review confirmatory evidence submitted by Reata in response to concerns raised by the regulator.
“If it gets approved, it's really good for patients,” Ben-Maimon said. “These patients have nothing.”
Reata declined to comment.
https://www.biospace.com/article/reata-friedreich-s-ataxia-patients-await-potential-first-approval/
Why Celldex Therapeutics Shares Are Trading Higher
Celldex Therapeutics Inc (NASDAQ: CLDX) announced updated data from its Phase 1b trial of barzolvolimab in patients with moderate to severe chronic spontaneous urticaria (CSU) refractory to antihistamines.
CSU is characterized by the occurrence of hives or wheals for six weeks or longer without identifiable specific triggers or causes.
Meaningful symptom improvement, measured through the urticaria activity score over 7 days (UAS7), was achieved across all dose levels evaluated with sustained activity observed with the 1.5 mg/kg and greater dose levels.
Mean UAS7 reduction at week 12 was 67% in the 1.5 mg/kg dose group (n=8), 67% in the 3.0 mg/kg dose group (n=9), and 82% in the 4.5 mg/kg dose group (n=9).
Complete response as measured by UAS7=0 was 56% in patients treated with the 1.5 mg/kg, 3.0 mg/kg, and 4.5 mg/kg doses at week 12.
At week 24, 16 weeks after the last dose, 53% of all patients treated with the 1.5 mg/kg and 3.0 mg/kg doses (additional follow-up ongoing in 4.5 mg/kg dose) had a complete response.
Data exhibits that multiple doses of barzolvolimab resulted in rapid dose-dependent decreases in itch and hives with durable and prolonged symptom control.
Rapid onset of responses after initial dosing and sustained durability were observed; onset as early as one week after the first dose and prolonged symptom control in some patients for up to 24 weeks.
Tryptase suppression, indicative of mast cell depletion, paralleled symptom improvement, demonstrating the impact of mast cell depletion on CSU disease activity.
Barzolvolimab was well tolerated with a favorable safety profile; the effects of multiple-dose administration were consistent with observations in single-dose studies.
Irenic: Letter to Theravance Re Need for Review
Despite Months of Private Engagement From Irenic and Presumably Other Investors, Chairman & CEO Rick E. Winningham and Theravance’s Board Refuse to Act in Shareholders’ Best Interests
Notes Theravance’s Total Shareholder Returns are -50% Since Its 2014 Separation and the Company Trades at a Massive Discount Due to Investors’ Lack of Confidence in Leadership
Encourages the Board to Reconsider Irenic’s Suggested Actions, Including Appointing a Shareholder Representative, Modernizing Entrenching Governance Policies and Returning ~$300 Million in Excess Cash
Sees Clear Path to Unlock Nearly $21 Per Share in Value if the Board Adopts Irenic’s Suggestions
Irenic Capital Management, LP, a top shareholder of Theravance Biopharma, Inc. (NASDAQ: TBPH), today released the below letter.
This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20230227005341/en/
***
February 27, 2023
Theravance Biopharma, Inc.
901 Gateway Boulevard
South San Francisco, CA 94080
Attn: The Board of Directors
Subject: The Need for Governance and Strategic Change Following Years of Losses and Underperformance
Dear Members of the Board of Directors (the "Board"),
Irenic Capital Management LP and its limited partners (together with its affiliates, "Irenic" or "we") own approximately 4.2% of the outstanding shares of Theravance Biopharma, Inc. ("Theravance" or the "Company"), making us one of the Company’s largest shareholders. We invested in Theravance because we believe the Company is worth substantially more than its current market value. In fact, we believe Theravance is worth nearly $21 per share as compared to its current trading price of only $9.87.1
Unlike value in many biotechnology companies, much of Theravance’s value – in fact, value in excess of its entire market capitalization – is in concrete, commercialized assets and not dependent on future trials or novel discoveries. Approximately 49% of Theravance’s market value, or $4.80,2 is in cash on the balance sheet and another $6.29 of value can be ascribed to the Company’s stake in YUPELRI ("Yupelri"). Another $4.80 is in milestone and royalty payments associated with Yupelri and GSK plc’s TRELEGY ELLIPTA ("Trelegy"). In short, even before considering the more speculative value ($5.05 probability-weighted) associated with the Company’s ownership of ampreloxetine (pending Phase III trial), Theravance is worth well in excess of its trading price. We detail our analysis of Theravance’s value below and in the Appendix to this letter.
Syneos Health eyes sale of company as contract backlog shrinks-sources
Syneos Health Inc is making a new effort to sell itself after a reduced backlog of contracts for providing clinical research to drug developers led to a 52% plunge in its shares over the past year, according to people familiar with the matter.
Reuters reported in March 2020 that Syneos was working with investment bank Centerview Partners LLC to explore a sale. The market disruption triggered by the onset of the COVID-19 pandemic prompted Syneos to abandon those sale deliberations, according to four sources familiar with the discussions.
Merck will appeal EU rejection of COVID drug Lagevrio
Merck & Co has said it will ask the EMA’s human medicines committee (CHMP) to look again at a decision not to recommend approval of its antiviral Lagevrio for treating some people with COVID-19.
Along with development partner Ridgeback Therapeutics, the US pharma group has said that it will appeal the decision and request a re-examination of the CHMP’s opinion, as it “does not reflect the compelling data” for the drug.
The EMA started a regulatory review of Lagevrio back in November 2021, shortly after the drug was approved for marketing in the UK as a treatment for people with mild to moderate COVID-19 who are at increased risk of developing severe disease.
At the time, oral antivirals like Lagevrio and Pfizer’s Paxlovid (nirmatrelvir/ritonavir) were being hailed as a key weapon in the fight against COVID-19, as they could be delivered to patients outside hospital - unlike therapies such as Gilead Sciences’ intravenously-administered antiviral Veklury (remdesivir).
Merck applied for approval of Lagevrio in the EU on the back of data from the MOVe-OUT trial, which showed a significant 50% reduced risk of hospitalisation or death compared to placebo, cutting the rate to 7% from 14% in adults with COVID-19 who are not receiving supplemental oxygen and who are at increased risk of developing severe COVID-19.
Other studies have not backed up that efficacy signal, however. Last year, the 25,000-subject PANORAMIC trial compared Lagevrio (molnupiravir) to placebo in people at risk of severe COVID showed that Lagevrio hastened the time to recovery from COVID-19 by around six days, but was no better than placebo at keeping patients out of hospital: the primary objective of the trial.
In its recommendation, the CHMP has said that, based on the totality of data, it was not possible to say that Lagevrio can “reduce the risk of hospitalisation or death or shorten the duration of illness or time to recovery in adults at risk of severe disease.”
It also said it was not possible to identify a group of patients who might benefit from the drug.
In its fourth-quarter results update, Merck projected sales of Lagevrio will be around $1 billion this year, down from a peak of nearly $5.7 billion last year.
“Data generated from the […] MOVe-OUT trial and from real-world studies demonstrate the positive impact that Lagevrio can provide for patients by reducing the risk of hospitalisation and death among adults at increased risk for severe disease,” said Merck’s head of R&D, Dean Li.
He added that more than four million patients worldwide have been treated with Lagevrio, which is authorised for use in more than 25 countries worldwide.
The benefit of Lagevrio has, however, also been called into question by health technology assessment (HTA) agencies, including NICE in the UK and ICER in the US, which have both concluded the drug’s benefits do not outweigh its cost.
https://pharmaphorum.com/news/merck-will-appeal-eu-rejection-covid-drug-lagevrio
J&J gets restricted label for PARP drug Akeega in EU
Johnson & Johnson’s entry into the PARP inhibitor market with prostate cancer therapy Akeega has started with a disappointing ruling in the EU.
The EMA’s human medicines committee has recommended approval for Akeega, a fixed-dose combination of J&J’s PARP drug Zejula (niraparib) and androgen inhibitor Zytiga (abiraterone acetate), in patients with metastatic castration-resistant prostate cancer (mCRPC).
In a setback for J&J’s Janssen-Cilag unit, however, the CHMP has said it recommends limiting use of Akeega to patients with BRCA1/2 mutations, which will put the drug at a disadvantage against AstraZeneca and Merck & Co’s rival PARP inhibitor Lynparza (olaparib).
In December, AZ and Merck claimed EU approval for the combination of Lynparza with Zytiga in an all-comer mCRPC patient population, allowing the regimen to be used without the need to test for mutations.
Janssen said that if fully approved by the European Commission – which usually follows a CHMP recommendation – Akeega will be the first dual action tablet in the EU for first-line treatment of adults with BRCA-positive mCRPC.
The question now is whether the convenience of a two-in-one tablet will be enough to offset the need for genomic testing of tumours and encourage take-up of the new drug.
J&J has rights to niraparib in prostate cancer under the terms of a licensing deal with its original developer Tesaro, signed in 2016, ahead of Tesaro’s acquisition by GSK. Rights to all other indications – including ovarian, fallopian tube, and peritoneal cancers – are owned by GSK.
The CHMP recommendation follows a phase 2 trial of Akeega, called MAGNITUDE, which revealed that the addition of niraparib to Zytiga plus prednisone or prednisolone significantly improved radiographic progression-free survival (rPFS) by 45% compared to standard of care in untreated mCRPC patients with BRCA1/2 mutations.
Updated results from MAGNITUDE were reported at the ASCO GU congress earlier this month, showing a trend towards improved overall survival, but no significant effect of the drug combination in mCRPC patients without homologous recombination repair (HRR) mutations, of which BRCA accounts for around half.
J&J and the investigators said the results were evidence that genomic testing of mCRPC patients remains critical.
“In recent years, we’ve focused on precision medicine in prostate cancer because we know patients with gene mutations, such as BRCA1/2, face a worse prognosis than those without,” commented Martin Vogel, Janssen-Cilag’s head of oncology for the EMEA region.
“The positive CHMP opinion reinforces the benefit of this niraparib combination and marks an important milestone in addressing BRCA1/2 mutations as we continue to drive progress towards changing the outlook for patients with mCRPC,” he added.
Analysts think a stronger challenge to Lynparza in first-line mCRPC could come from another PARP drug, Pfizer’s Talzenna (talazoparib) combined with Xtandi (enzalutamide), which reported new data from the TALAPRO-2 study at ASCO GU, including a 37% reduction in rPFS in an all-comer population.
https://pharmaphorum.com/news/jj-gets-restricted-label-parp-drug-akeega-eu
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