India's Torrent Pharma in talks with CVC, Bain Capital for Cipla bid- sources

 India's Torrent Pharmaceuticals is in talks with private equity funds CVC Capital Partners and Bain Capital to raise up to $1.5 billion to bid for India's Cipla, according to three sources with direct knowledge of the matter.

Torrent and Blackstone are among those interested to acquire a stake in Cipla, India's third-biggest drugmaker by sales, in what could be the largest pharma deal in India ever.

Cipla's founding family is keen to sell their 33.4% holding entirely, sources say, and any bid will also trigger an open offer for another 26% stake, as per Indian regulations. That translates to a $6.75 - $7 billion deal, Bernstein estimated in an Aug. 30 report.

Torrent is likely to reach a decision to finalize its consortium financing partner in the next few days, said the first source.

Bain and Blackstone declined to comment while Cipla, Torrent and CVC did not respond to comments. The Economic Times first reported CVC's talks with Torrent on Monday.

Cipla also exports medicines to North America and South Africa, and sells generic drugs to treat illnesses like cold, fever and headaches. It competes with global majors Pfizer and Abbott, among others, in the world's most populous nation whose pharmaceutical market is expected to reach $130 billion by 2030, from $50 billion currently.

Torrent, whose market cap is 54% lower than Cipla's $11.9 billion, is present in more than 40 countries and sells medicines related to diabetes, pain management, gynaecology, oncology and anti-infective segments as per its website.

Torrent and Blackstone both have submitted non-binding bids for Cipla, sources say.

Foreign banks, including Morgan Stanley and Barclays are also in talks with Torrent to arrange potential debt financing for the deal, the second and third source said.

Barclays declined to comment while Morgan Stanley did not immediately respond.

The second source said Cipla is likely to be more keen on getting a strategic partner on board, like Torrent, instead of a pure financial investor, though a final decision was not likely soon.

A Bernstein report in August flagged possible antitrust scrutiny and requirement to divest brands when combined market shares are high. It added that product overlap between Cipla and Torrent is "manageable" as there were only four overlaps at the molecule level where the "combined sales share would cross the 90% mark."

https://www.marketscreener.com/quote/stock/BLACKSTONE-INC-60951400/news/India-s-Torrent-Pharma-in-talks-with-CVC-Bain-Capital-for-Cipla-bid-sources-44863748/

Novartis: Sandoz positive CHMP opinion for breast and gastric cancer biosimilar

 

• Positive CHMP opinion based on comprehensive package of analytical, pre-clinical and clinical data

• Breast and gastric cancers are among most common types of cancer, accounting together for nearly half a million new cases every year in Europe alone1,2

• Sandoz is committed to accelerating access to potentially life-changing treatments and continues to strengthen its oncology and supportive care portfolio

https://finance.yahoo.com/news/sandoz-receives-positive-chmp-opinion-051500565.html

Akili exits the prescription DTx market, slashing staff

 One of the pioneers of the prescription digital therapeutics (DTx) sector, Akili Interactive, has decided to abandon that approach and focus exclusively on a direct-to-consumer business.

The decision – which comes alongside a 40% reduction in staffing levels – is another example of the challenges facing companies trying to build a sustainable DTx business, faced with high entry hurdles and uncertainties in reimbursement, payer acceptance, and healthcare provider adoption of prescription DTx products.

That challenging environment has already led to the demise of Pear Therapeutics, despite having three FDA-approved prescription DTx products, as well as job cuts at other companies, including Better Therapeutics and Biofourmis.

In a statement, Akili said that it has been seeing good growth in consumer demand for the over-the-counter version of its flagship EndeavorRx DTx for attention deficit hyperactivity disorder (ADHD) in its first three months on the market, and will now pursue regulatory approvals for OTC labelling across its product range.

"Today, we are evolving our business to remove barriers for patients trying to access safe and effective non-drug treatment options," said Eddie Martucci, Akili's chief executive, adding that the move will reduce reliance on intermediaries and payers.

"We have the unique ability to offer consumers the same clinically-proven technology as the world's only FDA-approved prescription video game treatment, with the ease of access and convenience of a consumer tech product," he added.

"We believe that our shift to a consumer-led model across our business will maximise our reach in the ADHD patient community and allow us to potentially expand into other large markets, without many of the high cost centres of a prescription model."

EndeavorOTC was launched in June via Apple's App Store, shortly after Akili reported the results of a clinical trial showing that the DTx was effective as a treatment for adults with ADHD, as well as children.

The app is based on gameplay that challenges users to tap targets and navigate obstacles to boost attention and focus.

Since it was released on the App Store it has been downloaded by almost 126,000 users and has 4,170 active subscribers who spent more than $81 on average over the period, generating around $341,000 in revenues.

For comparison, the company achieved revenues of $323,000 in full-year 2022 pursuing its prescription model. For now, the prescription EndeavorRx product will remain available, while Akili works on switching it to OTC status, with a filing for that expected next year.

As might be expected, the job cuts are coming from the company's sales and market access teams, and will help to extend cash reserves out to 2025, said Akili. It now expects operating expenses to fall from $55 million to $60 million this year to between $42 million and $47 million next year.

https://pharmaphorum.com/news/akili-exits-prescription-dtx-market-slashing-staff

FDA capacity forces delay to Iovance's cell therapy

 Iovance Biotherapeutics is facing a three-month delay in the review of its lifileucel cell therapy for melanoma in the US, held up by "insufficient resources" at the FDA.

The new data has been extended from 25th November to 24th February next year, although Iovance said the FDA has said it will "expedite the remaining review for a potentially earlier approval date."

The biotech filed tumour-infiltrating lymphocyte (TIL) therapy lifileucel as a one-time, individualised therapy for people with advanced melanoma in May, and was awarded a priority, six-month review by the FDA, with no advisory committee meeting required.

Iovance said the priority review remains in place, adding that the FDA had reassured it that there were no major review issues with the marketing application and all pre-approval inspections of clinical, manufacturing, and testing sites have been completed. The delay resulted from a lack of capacity to deal with the response to a request for additional information.

It also said the FDA has no concerns with the TILVANCE-301 in frontline advanced melanoma, designed to be a confirmatory trial for accelerated approval, which should be "well underway" by the new decision date.

Iovance is leading the charge among biopharma companies trying to bring cell therapies to market for solid tumours and mirror the success achieved with CAR-Ts in haematological cancers.

Like a CAR-T, lifileucel is derived from lymphocytes that are harvested from individual patients, expanded in the lab, and then reinfused to fight the cancer. Unlike CAR-T therapies, however, the cells don't need to be genetically modified, merely exposed to IL-2 to activate them, which makes the manufacturing process shorter.

Iovance's filing covers the use of the therapy for patients with advanced melanoma who progressed on or after prior anti-PD-1/L1 therapy and targeted therapy, where applicable. There are currently no FDA-approved therapies in this treatment setting, according to the company.

Its filing is based on the results of the C-144-01 study, which showed lifileucel achieved a 36% objective response rate (ORR) with a duration of response of 36 months in these patients, leading to predictions of blockbuster sales for the cell therapy.

That initial optimism has been somewhat dented by follow-up data that raised questions about lifileucel's durability, with an ORR of 29% for a second cohort in the study and a duration of 10.4 months. GlobalData is currently predicting US sales will peak at around $722 million.

"We appreciate FDA management's efforts to expedite the remaining review so that we can bring lifileucel to critically ill patients with no other FDA-approved options after current standard of care," said Iovance's chief executive, Frederick Vogt.

"We are confident in the potential for lifileucel to redefine the treatment paradigm for these patients."

Shares in the company dipped on the delay, but were on the rise this morning as investors responded to the positive elements in the update and the agency's reported willingness to complete the review as quickly as possible.

https://pharmaphorum.com/news/fda-capacity-forces-delay-iovances-cell-therapy

As Impact of Substance Use Disorders Rise, so Do Innovative Solutions

 In July, the FDA approved a first-in-human clinical trial of a monoclonal antibody investigated by Cessation Therapeutics that aims to prevent fentanyl overdose. That same month, the regulator greenlighted an over-the-counter nasal spray formulation of naloxone—a staple in reversing opioid overdose since its FDA approval in 1971—from Harm Reduction Therapeutics, a nonprofit biopharma.

These are but two examples of a wide-ranging push to address the broader issue of substance use disorder (SUD). Currently, the National Institutes of Health’s clinical trial database lists 714 active studies investigating treatments for SUD.

“You can’t treat a dead person,” Cessation CEO Tracy Woody told BioSpace. “We are trying to keep these people alive and bridge them to other treatments.”

SUD is a disease that affects a person’s brain and behavior, leading to the uncontrollable use of harmful substances like alcohol, opioids and illicit drugs. More than 40 million Americans aged 12 or older had a SUD in 2019, according to 2020 data collected by the Substance Abuse and Mental Health Services Administration, and CDC data show that over 150 people die every day from overdoses related to synthetic opioids alone.

Here, BioSpace explores a few of the many drug development efforts that aim to reduce these tragic numbers.

Neutralizing Fentanyl

Dubbed CSX-1004, Cessation’s therapeutic works by neutralizing fentanyl molecules as they enter the bloodstream, preventing the opioid from impacting the brain and causing overdose. This effectively halts respiratory depression, which is fatal.

“We have done a lot of studies in nonhuman primates with our collaborators at Harvard to evaluate fentanyl-induced respiratory depression, and we showed with this antibody that a single dose could prevent the respiratory effects of fentanyl for about 30 days,” said Andy Barrett, CSO of Cessation Therapeutics.

Woody noted that a monoclonal antibody option for preventing overdose could also mean broader accessibility. Some treatments for substance use disorder, such as buprenorphine, are classified as controlled substances by the Drug Enforcement Agency, but a monoclonal antibody would not be, minimizing some barriers to access for clinics.

Lowering Costs to Increase Accessibility

Harm Reduction Therapeutics’ over-the-counter therapeutic, RiVive, is an opioid receptor antagonist that works similarly to generic naloxone nasal sprays currently available via prescription. Specifically, it prevents overdose by binding to opioid receptors, which reverse or block the effects of opioids that have been taken. This process helps to prevent respiratory depression.

Naloxone’s original approval required a prescription, which could be a potential barrier to accessing the life-saving drug as it required seeing a medical professional. The price of naloxone has also escalated in tandem with the opioid epidemic. For example, the price of a vial of injectable naloxone manufactured by Hospira increased 129% from 2014 to 2016, as reported in The New England Journal of Medicine.

A two-pack of Narcan, a name brand of naloxone, can cost $145 for uninsured patients, according to Naloxone Exchange. RiVive, on the other hand, is set to be available for $36 for a box of two doses. Ten percent of the cost goes to funding free doses for those who can’t afford it—the company is partnered with Remedy Alliance to donate 200,000 naloxone doses for distribution.

“Harm Reduction Therapeutics exists to fix a problem that, in an ideal market, wouldn’t exist,” Michael Hufford, the company’s co-founder and CEO, told BioSpace. “In an ideal market, the price of an old, established drug like naloxone should fall [over time]. It didn’t, so we helped correct that.”

Blocking the Cravings that Drive Addiction

Focusing on another addictive substance, alcohol, Addex Therapeutics and Indivior are looking to reduce the desire to drink in the first place.

“In the U.S. alone, there are about 14 million people diagnosed with alcohol use disorder, and the number one issue is cravings,” Indivior CEO Mark Crossley told BioSpace. “If we could intervene on cravings, we think there’s a chance to reduce alcohol usage.”

Alcohol intake disrupts the brain’s GABA transmission, particularly the GABAB receptor, which is associated with the development and maintenance of addiction. Robert Lütjens, head of discovery–biology at Addex, said that agonists of the receptor have been studied extensively in the context of substance use.

“[Agonists] that have been tested in preclinical models have shown that GABAB receptor activation can reduce addiction and addictive behavior,” he told BioSpace.

However, approved agonists, such as Baclofen, come with side effects like sedation, and patients can become tolerant, requiring higher dosing, Lütjens said. To avoid these drawbacks, Addex and Indivior entered into a strategic collaboration to develop GABAB-positive allosteric modulators (PAMs) for alcohol use disorder.

PAMs differ from agonists in that they work to enhance the activity of GABAB receptors only when the GABA neurotransmitter activates the receptor.

“In my mind, I think of [PAMs] as working when the patient needs it,” Crossley said. “The neat thing about a PAM is that it doesn’t sit on the receptor all the time, which helps to resolve a lot of the side effects.”

The companies plan to have a lead asset from their GABAB PAM development program ready for clinical trials in Q4 of 2023, Crossley added.

https://www.biospace.com/article/as-impact-of-substance-use-disorders-rise-so-do-innovative-solutions/

Despite Early Success, Karyopharm’s Selinexor Faces Uncertain Path

 Ever since Karyopharm Therapeutics gained accelerated FDA approval for selinexor combined with dexamethasone in relapsed or refractory multiple myeloma, the Massachusetts–based company has been conducting clinical trials with an eye toward increasing its market share, primarily in the oncology space. But multiple hurdles are hindering its chances of success.

When selinexor was first approved in July 2019 for relapsed or refractory multiple myeloma (RRMM), several clinical trial obstacles limited its use even within the multiple myeloma space. While the 8.6-month median overall survival (OS) rate for those treated with the selinexor regimen in the Phase IIb STORM trial was enough to secure FDA approval, when compared to the approximately 9-month median overall survival rates for RRMM with existing treatments, this efficacy may not be enough for uninterrupted success in the market.

Selinexor’s original approval was for adults with RRMM who have unsuccessfully tried at least four prior therapies and have disease that is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody. This leaves Karyopharm with a smaller patient pool than treatments approved in the first-line multiple myeloma setting.

As of 2019, there were nine drugs approved for RRMM in the United States. In a 2018 meta-analysis on RRMM treatment, some of these regimens showed more efficacy than selinexor in terms of median OS. For instance, in the POLLUX trial, Janssen and Genmab’s daratumumab and Bristol Myers Squibb’s lenalidomide combined with dexamethasone led to a median OS rate of 67.6 months, compared to lenalidomide and dexamethasone alone, which led to a median OS of 51.8 months in patients treated with one or more previous lines of therapy.

In 2020, Karyopharm received further approvals for selinexor in multiple myeloma—with bortezomib and dexamethasone—after at least one prior therapy, and relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The company is also looking for alternative selinexor regimens to treat these indications and is investigating the drug in other disease states including endometrial cancer and myelofibrosis.

When looking at the rate of new cases for these four cancers, endometrial cancer has the most promising patient pool based on incidence alone. At 35.7 cases per 100,000 people, the incidence rate would far eclipse the other three indications, with relapsed or refractory multiple myeloma affecting 4.4 per 100,000 people in 2016; diffuse large B-cell lymphoma 4.68 people per 100,000 in 2021; and myelofibrosis 0.47 per 100,000 in 2014. But endometrial cancer is considered a solid tumor and this is still unprecedented territory for selinexor, which has primarily demonstrated proof of efficacy in hematologic malignancies. Most of Karyopharm’s trials have been conducted in hematologic cancers.

Though Karyopharm’s pivotal SIENDO trial for endometrial cancer failed to yield clinically meaningful results, the company stated in its Q2, 2023 financial report that a subgroup of patients with TP53 wild-type cancer could potentially see more significant results. Still, this trial update could limit selinexor’s patient population reach and market share even more.

While Karyopharm’s successes with selinexor have proven to be newsworthy, there is still much to consider when analyzing the company’s future trajectory. Therefore, the final endometrial cancer trial results will be pivotal in determining Karyopharm’s direction over the next two to three years.

https://www.biospace.com/article/despite-early-success-karyopharm-s-selinexor-faces-uncertain-path-to-expansion/

FDA Action Alert: ARS Pharma, Appili, Ocuphire and BrainStorm

 The FDA is gearing up for a busy second half of September with three target action dates and a highly-anticipated advisory committee meeting for an investigational amyotrophic lateral sclerosis (ALS) treatment.

ARS Pharma Anticipates Decision on Non-injectable Epinephrine Therapy

Following a three-month delay, the FDA on Sept. 19 is set to release its decision on ARS Pharmaceuticals’ New Drug Application for neffy, a nasal epinephrine spray being proposed to treat type 1 allergic reactions, including anaphylaxis.

The San Diego–based biotech is supporting its regulatory bid with four primary registrational studies, in which neffy elicited a pharmacokinetic profile that was within the range of approved injectable formulations of epinephrine. The FDA accepted the NDA in October 2022.

The majority of adverse events associated with neffy were mild, according to the announcement. There was no meaningful nasal irritation or pain associated with the investigational nasal spray.

In May 2023, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted in favor of neffy’s approval. Split 16–6, the panel of external experts deemed that ARS’s data demonstrated a favorable risk-benefit profile for neffy in adults. The turnout was slightly better in the pediatric setting, with the Committee voting 17–5 in favor of allowing neffy for children aged 18 years and younger. The FDA is not required to follow the advice of its advisory committees, though it often does.

In briefing documents published ahead of the May 2023 meeting, the regulator’s staffers flagged a lack of clinical data backing neffy. In particular, the reviewers stated that relying on pharmacokinetic and pharmacodynamic data—and the similarity of these profiles to approved epinephrine injections—could be an unreliable benchmark of efficacy and safety, especially as data for injections are scarce to begin with. Differences in the routes of administration may also affect these comparisons.

If approved, neffy would be the first non-injectable epinephrine therapy for allergies in the United States.

Appili Anticipates Decision on Liquid Reformulation of Metronidazole

Appili Therapeutics expects a verdict on its liquid oral reformulation of the antibiotic metronidazole, ATI-1501, on or before September 23.

The company has licensed ATI-1501 to Saptalis Pharmaceuticals and announced during an August 2023 earnings report that it expects to receive milestone payments in the coming quarters, based on Saptalis’ commercialization plans.

The FDA accepted the NDA for ATI-1501 in February 2023.

With over 10 million annual prescriptions in the U.S., metronidazole is a widely prescribed front-line oral antibiotic used commonly for parasitic and anaerobic bacterial infections, according to Appili’s website. Currently, metronidazole is only approved in tablet form, which poses medication barriers for very young patients and those who have difficulties swallowing, especially the elderly.

In these cases, the tablets are crushed and resuspended in food or drinks, which could result in dosing errors. Mixing metronidazole with food also does little to mask the drug’s bitter taste, which could turn patients off and lead to lower medication adherence.

Apilli’s reformulated liquid suspension of metronidazole not only masks its bitter taste, but also makes the medicine easier to administer, according to the company.

If approved, ATI-1501 could present a “convenient treatment option for those suffering devastating infections,” president and CEO Don Cilla said in a statement at the time of the NDA acceptance.

FDA to Decide on Ocuphire’s Eye Drops to Reverse Eye Dilation

The FDA is scheduled to decide next week on Ocuphire’s NDA proposing Nyxol (phentolamine ophthalmic solution 0.75%) for the treatment of pharmacologically-induced mydriasis, or pupil dilation. The regulator’s deadline is Sept. 28.

Using medication to induce eye dilation is a common clinical procedure, with around 100 million operations carried out in the U.S. annually. These are usually part of routine checkups, monitoring for eye diseases and preparation for eye surgeries.

Depending on patients’ eye color and other factors, artificial dilation can persist from six to 24 hours, during which time the eyes are more sensitive to light and have greater difficulty focusing on near objects. This can make it difficult for patients to read, work or drive. There are currently no approved agents to reverse mydriasis.

Ocuphire’s Nyxol is a stable and preservative-free ophthalmic formulation of phentolamine, which works by blocking α1 receptors on the iris dilator muscles. This, in turn, has the effect of modulating pupil size without affecting the ciliary muscles.

The Michigan–based biotech is supporting Nyxol’s NDA with data from its MIRA clinical development program, which enrolled more than 600 patients across four trials. Overall, the studies showed that Nyxol was significantly better than placebo at rapidly restoring baseline pupil diameter, which occurred from 60 to 90 minutes after administration.

The MIRA trials also demonstrated a favorable safety and tolerability profile for Nyxol in this indication. Pediatric data showed that Nyxol could also potentially be used to reverse dilation in children aged 3 years and above.

Aside from mydriasis, Ocuphire is also developing Nyxol for presbyopia and night vision disturbances.

BrainStorm’s NurOwn to Face Advisory Committee

On Sept. 27, BrainStorm Cell Therapeutics’ investigational ALS therapy NurOwn (autologous bone marrow-derived mesenchymal stromal cells induced to secrete neurotrophic factors) will face the FDA’s Cellular, Tissue and Gene Therapies advisory committee.

The panel of external experts will evaluate the body of data supporting NurOwn and decide whether its benefit-risk profile is favorable and supports approval.

BrainStorm first tried seeking approval for NurOwn in 2021 but was turned back by the FDA, which stated that the company’s Phase III trial did not meet the evidence threshold required to support a Biologics License Application. The Israel- and New York–based biotech tried again in November 2022, but was met with a Refusal to File Letter, which flagged statistical and manufacturing concerns with the resubmission.

Following its second regulatory stumble, BrainStorm decided to leverage the FDA’s File Over Protest procedure to request an adcomm meeting—and to hopefully secure the fastest way to a regulatory verdict.

The ALS space has already seen the approval this year of Biogen and Ionis’ Qalsody (tofersen), which in May 2023 won accelerated approval for a specific type of ALS based on biomarker data. In particular, the pharma partners showed that Qalsody reduced levels of the neurofilament light chain and SOD1 protein, both of which could be indicative of clinical effect. A few months earlier, an advisory committee voted unanimously that these biomarkers could indeed be reasonable predictors of Qalsody’s therapeutic benefit.

In July 2023, a few months after securing the adcomm meeting, BrainStorm released Phase III data showing that NurOwn could also significantly lower neurodegeneration biomarkers, including neurofilament light chain.

https://www.biospace.com/article/fda-action-alert-ars-pharma-appili-ocuphire-and-brainstorm/