Bristol Myers Squibb(BMY) offered to buyMirati Therapeutics(MRTX) for up to $5.8 billion, but MRTX stock tumbled Monday on the lowball bid.
The deal values Mirati stock at $58 per share, representing a total $4.8 billion takeover price. But MRTX stock closed at 60.20 on Friday.
On Thursday, a Food and Drug Administration panel said the evidence backing Amgen's (AMGN) lung cancer treatment, Lumakras, a rival to a Mirati drug called Krazati, isn't sufficient to support its accelerated approval. Now, it's unclear whether the FDA will allow Amgen to keep Lumakras on the market. The same day, Bloomberg reported Sanofi (SNY) was looking to buy Mirati, and MRTX stock rocketed more than 45%.
Bristol's offer includes a contingent value right worth $12 per share of MRTX stock. It will pay that if the FDA accepts an application for approval of Mirati's drug, MRTX1719. The company is testing that drug in patients with a form of lung cancer. That would bring the total deal value up to $5.8 billion.
6 of 11 Patients in the Pilot Phase Experienced a Partial Response, with 4 Confirmed; One PatientExperienced Resolution of the Hepatic Metastatic Lesion -
- Data Presented at AACR Special Conference on Pancreatic Cancer -
- Multi-Center, Randomized Phase 2 Study Currently Enrolling -
Last month,Wave Life Sciencessubmitteda clinical trial applicationfor WVE-006, which would be the first-ever RNA editing therapy to enter clinical development. If approved, the company plans to dose the first patients by the end of this year and have data in 2024.
“What’s important [with this application] is we’re showing [that] the field can see medicine rapidly moved from ideation to the clinic,” Paul Bolno, Wave’s CEO, told BioSpace.
WVE-006 is designed to restore production and circulation of functional, wildtype alpha-1 antitrypsin (AAT) protein and reduce levels of mutant Z-AAT protein in oder to treat alpha-1 antitrypsin deficiency (AATD)–related lung or liver disease.
Paul Bolno
“It’s unique because we’re taking a broken protein, we’re fixing it, and we’re showing that when you fix the transcript, you get restored levels of protein and that protein is functional,” Bolno said. “We’re going to responsibly bring the first program into the clinic that we believe has the profile to change how patients are treated.”
WVE-006 relies on RNA editing instead of DNA editing. Bolno stressed that RNA editing is inherently safer to test since it is reversible and does not permanently alter the genetic code. Wave has shown that the program does not produce any bystander edits, he said, meaning it doesn’t hit unintended targets around the target site or generate unintended proteins, known as isoforms.
This is in contrast to DNA editing, which can induce unintended bystander edits or immune responses, Bolno said. This all means that Wave can include healthy volunteers in its trials. “Rapidly completing volunteer cohorts will enable the initiation of patient cohorts at optimized dose levels,” Bolno said during Wave’s R&D Day on September 28.
He added that the company feels comfortable moving WVE-006 into the clinic because of the positive results from its preclinical studies and Wave’s careful characterization of the profile and chemistry of the program. In mouse models, the candidate led to restored AAT protein “well over 11 micromolar,” improvement in several markers of liver disease and inhibition of neutrophil elastase, Anne Marie Li-Kwai-Cheung, Wave’s chief development officer, said in a statement.
Industry Poised to Accelerate
Wave’s clinical trial application has generated renewed excitement around RNA editing. Salim Syed, a managing director and senior biotechnology analyst at Mizuho Group who covers the company, said the modality will continue to garner attention.
“Investors have been quite focused on WVE-006 for AATD for some time, though [they] haven’t really engaged too much with the story given it was always a bit too far away,” he told BioSpace, adding that it’s nice to finally see this program enter the clinic with data anticipated in 2024. “It has potential to be a very important readout for the company.”
Still, Syed cautioned that as with any "first" in human testing, observers will be keeping an especially close watch on safety indicators.
“With editing of any sort . . . you’d want to make sure that the editing is highly specific and there is no evidence of bystander editing,” he said. Additionally, he noted, “You’d want to understand what durability and re-dosing may look like for WVE-006 and, in general, for any RNA editing therapy.”
Daniel de Boer, founder and CEO of ProQR Therapeutics, another RNA editing biotech, also expressed enthusiasm about the progress in the field.
“We are excited about the RNA editing space and the potential for a new class of medicines to evolve and bring us closer to improving patients’ lives with this technology,” he told BioSpace.
In 2014, ProQR discovered a technology—called Axiomer—that uses naturally occurring molecular machinery within the body to mediate single nucleotide changes to RNA in a highly specific and targeted way. The company holds a broad patent estate protecting the use of oligonucleotides to recruit endogenous ADAR (Adenosine Deaminase Acting on RNA).
“Our technology has shown promising editing efficiency in many different genes, both in vitro as well as in vivo,” de Boer said. In addition to 10 targets being developed in partnership with Eli Lilly, ProQR has selected two initial targets for its wholly-owned pipeline programs. “We are well-positioned to advance our Axiomer platform over the next several months,” de Boer said, with a clear development path for its two programs, AX-0810 for cholestatic diseases and AX-1412 for cardiovascular diseases. “Both have target-specific biomarkers with strong translatability in the clinic,” he said. De Boer said the team looks forward to sharing more data on the targets in the coming months.
Lilly is not the only large biopharma company investing in RNA editing to support its pipeline. British multinational GSK is partnered with Wave on eight programs, including WVE-006.
“In my 30-year career of discovering and developing medicines, I’ve never witnessed such remarkable advances in our understanding of human biology and the incredible possibilities they bring to unite science and tech together to get ahead of disease,” Tony Wood, GSK’s chief scientific officer said during Wave’s R&D Day. “Right now, we find ourselves at an inflection point with RNA and its role in broader biology.”
As an example, Wood said that oligonucleotides, the tiny molecules used in Wave’s RNA editing medicine, have traditionally been used to target rare diseases but are now being researched to potentially treat more prevalent ones.
Bolno echoed this statement, predicting that a pipeline of products will begin to deliver on the power of RNA editing over the next five years, and not just for rare diseases but for prevalent ones where he noted that the reversible nature of RNA editing will be important.
“This is no longer an alternate reality,” Bolno said. “We see lots of companies trying to say, ‘Imagine the future if…’ We don’t really have to imagine. We’re delivering the future.”
In recent years, the FDA has granted approval to some novel drugs despite failed clinical trials or minimal evidence. Guidance issued in rare or uniformly fatal diseases likeamyotrophic lateral sclerosis and the approvals of Aduhelm in Alzheimer’s and Qalsody in ALS indicate a trend toward greater regulatory flexibility.
But is the agency moving too quickly? Recent research from Stanford, Oregon State University and the McGovern School of Medicine found that the FDA is greenlighting more novel drugs based on single clinical trials, and pharmaceutical companies are only required to share the results from two trials, “leaving questions about why they chose those two for submission and what happened in the other trials,” study co-author Veronica Irvin said in Medical Xpress.
Another study published in The BMJ in July 2023 found that less than half of new drugs being approved in the U.S. and Europe are adding true therapeutic value to patients, with the largest culprit being cancer therapies.
On the other hand, cases like that of Takeda’s mobocertinib—which the Japanese pharma pulled from U.S. and global markets last week following discussions with the FDA after it failed to meet the primary endpoint in a confirmatory trial—and Covis Pharma’s preterm birth drug Makena, for which the FDA withdrew approval in April, point to an effort by the regulator to clamp down on ineffective medicines.
BioSpace looks at half a dozen therapies approved by the FDA during the past seven years despite failure to meet Phase III endpoints or provide consistent proof of efficacy.
Ipsen’s Sohonos
Most recently, on August 16, the FDA granted approval to Ipsen’s Sohonos (palovarotene) for the ultra-rare genetic disease fibrodysplasia ossificans progressive (FOP) after the agency noted the drug “crossed the prespecified futility boundary” in a Phase III trial.
The approval is the culmination of a long and winding path for Ipsen. The FDA rejected palovarotene’s first New Drug Application in December 2022 due to a previous request for additional clinical trial data. The agency accepted Ipsen’s resubmitted NDA in March of this year.
Ipsen has maintained that the Phase III result was due to statistical discrepancies and the biases that come with using historical controls. In briefing documents released ahead of a June advisory committee meeting, the FDA appeared to agree, stating, “We think it is reasonable to consider alternative, more appropriate analyses to assess evidence of efficacy.” So did the external advisers, who voted 11-3 that palovarotene’s benefits outweighed its associated risks.
Sarepta’s Elevidys
In June, the FDA approved Sarepta’s Elevidys as the first gene therapy for Duchenne muscular dystrophy (DMD) even though the medicine failed to meet the primary functional endpoint in a randomized trial. Elevidys won accelerated approval based on data showing it increased the expression of the micro-dystrophin protein—a biomarker the agency determined is “reasonably likely to predict clinical benefit” in DMD patients four to five years of age.
As a condition of the approval, the FDA is requiring Sarepta to complete a study to confirm Elevidys’ clinical benefit. ClinicalTrials.gov lists a Phase I/II study intended to evaluate the therapy’s safety and efficacy, with an expected completion date of April 2026.
Biogen’s Qalsody
In April, Biogen won FDA approval for Qalsody (tofersen) to treat patients with superoxide dismutase 1 (SOD1)-ALS, a rare subtype of the fatal neurodegenerative disease. Like Elevidys, Qalsody went through the FDA’s accelerated approval pathway, which gives the regulator license to grant approval when there is an unmet medical need and a drug is shown to have an effect on a surrogate endpoint. In the case of Qalsody, this endpoint was neurofilament light chain (NfL).
Biogen sought approval of Qalsody based on NfL after the drug failed to meet the primary endpoint of a statistically significant change from baseline to week 28 on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in the Phase III VALOR study. The company did publish combined analyses of 12-month VALOR data and the accompanying open-label extension study showing that earlier initiation of Qalsody slowed decline in function and strength in SOD1-ALS patients.
Biogen and Eisai’s Aduhelm
One of the most controversial FDA approvals in recent history, Biogen and Eisai got the nod for Aduhelm (aducanumab) in June 2021, setting off a firestorm of commentary in both scientific and mainstream publications about the drug’s relative merits. In March 2019, Biogen and Eisai had announced they would abandon aducanumab after a futility analysis suggested it was unlikely to work. A few months later, the partners did an about-face, saying a thorough data analysis found that the Phase III EMERGE trial hit the primary endpoint in a subpopulation at the highest dose.
In its approval announcement, the FDA noted that “patients receiving [Aduhelm] had significant dose-and time-dependent reduction of amyloid beta plaque,” a well-known Alzheimer’s biomarker, while patients in the control arm of Biogen’s three studies had no reduction of these plaques.
The FDA granted Aduhelm approval even after a near-unanimous vote by its Peripheral and Central Nervous System Drugs Advisory Committee that there was insufficient evidence to demonstrate the drug slowed cognitive decline. Three committee members ultimately resigned over the decision.
Jazz Pharmaceuticals and PharmaMar’s Zepzelca
While Zepzelca (lurbinectedin) showed enough efficacy in an open-label monotherapy study to win accelerated FDA approval in small cell lung cancer (SCLC) that had progressed on or after platinum-based chemotherapy, it failed to meet the endpoint in a much larger Phase III trial just six months later.
In June 2020, Jazz Pharmaceuticals and partner PharmaMar secured approval for Zepzelca based on an overall response rate of 35% and duration of response of 5.3 months in a trial of 105 patients. However, in December of the same year, Zepzelca combined with doxorubicin was found to make no significant difference to overall survival when the same combination was compared with the physician’s choice of topotecan or cyclophosphamide/doxorubicin/vincristine in a trial of 613 patients. Zepzelca remains on the market and earned Jazz $70.3 million in sales in the second quarter of this year.
Acadia’s Nuplazid
An early example of the trend toward greater regulatory flexibility came in 2016 when the FDA approved Acadia Pharmaceuticals’ Nuplazid (pimavanserin) to treat hallucinations and delusions associated with psychosis in Parkinson’s disease. The first approved medicine for this indication, Nuplazid got the FDA’s nod based on efficacy shown in a six-week clinical trial of 199 participants, although it failed two other trials, PBS reported.
An atypical antipsychotic, Nuplazid’s label came with a boxed warning due to an increased risk of death associated with this drug class in older people with dementia-related psychosis. The regulator noted at the time that no atypical antipsychotic was approved for this patient population.
Two years later, CNNreported that the FDA was taking another look at Nuplazid’s safety profile after monitoring showed it was associated with more than 700 deaths. In August 2022, the FDA rejected a supplemental New Drug Application for pimavanserin for hallucinations linked to Alzheimer's disease psychosis due to “interpretability” issues with the study data.
As Streptococcus A cases continue to be prevalent internationally, a new nasal vaccine could provide long-term protection from the deadly bacteria.
Associate Professor Manisha Pandey, Professor Michael Good, and their team from Griffith University's Institute for Glycomics, are leading the development of a Strep A vaccine which is currently in Phase 1 clinical trials in Canada and quickly advancing to Phase 2 efficacy trials.
The team's new preclinical research, recently published in Nature Communications, shows an experimental liposome-based vaccine approach incorporating a conserved M-protein epitope from Strep A and an immunostimulatory glycolipid (3D(6-acyl) PHAD) administered via the nasal passage, can provide long-term mucosal protection against Strep A.
Lead author Dr Victoria Ozberk said studies have shown most pathogens enter or colonise via the soft tissue in the upper respiratory tract, which is essentially the highway to the rest of the body.
"This has the potential to be a world-first as there are currently no subunit vaccines that target the upper respiratory tract due to a lack of licenced immunostimulants suitable for human use," Dr Ozberk said.
"We demonstrated that a liposomal mucosal vaccination strategy can induce robust local protective immunity."
Associate Professor Pandey said the team found PHAD plays an augmenting role in inducing enduring humoral and cellular immunity, which was evident for at least one-year post-vaccination.
"The longevity of immune response is a critical hallmark of successful vaccination and therefore the findings from this study are highly significant," she said.
Professor Good said: "In the future, this vaccine platform could pave the way for other mucosal pathogens."
Group A Streptococcus is a global human pathogen that leads to a wide range of infections from illnesses such as mild pharyngitis and impetigo to invasive diseases such as toxic shock syndrome, necrotising fasciitis, and cellulitis.
Professor Mark von Itzstein AO, Director of the Institute for Glycomics, welcomed these research findings.
"This platform provides a real shot at developing a new direction for vaccine discovery against significant infectious pathogens that cause serious and life-threatening diseases," he said.
Immunity to Strep A takes several years to develop, and currently, there is no vaccine available.
Moreover, repeated infections can lead to the post-streptococcal sequelae of rheumatic fever and rheumatic heart disease, for which the Australian Indigenous population bears the highest disease burden globally.
Strep A causes 700 million human infections each year and there are more than 500,000 deaths globally.
The team has developed a Strep A vaccine which is currently being tested in a human clinical trial in Canada.
The paper 'A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils' has been published in Nature Communications.
Journal Reference:
Victoria Ozberk, Mehfuz Zaman, Ailin Lepletier, Sharareh Eskandari, Jacqualine Kaden, Jamie-Lee Mills, Ainslie Calcutt, Jessica Dooley, Yongbao Huo, Emma L. Langshaw, Glen C. Ulett, Michael R. Batzloff, Michael F. Good, Manisha Pandey. A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils. Nature Communications, 2023; 14 (1) DOI: 10.1038/s41467-023-41410-7
