Idorsia sets itself up for failure

 Idorsia’s faith in cenerimod might be understandable in the context of lupus recently becoming an area for deal-making interest. But the group’s decision to press on into phase 3 trials after cenerimod today flopped in phase 2 seems reckless, and potentially sets the project up for an even bigger failure later on.

True, Idorsia has plenty of cash to burn – over CHF1bn ($1.1bn) of short-term liquidity at the end of September, to be precise – but its investors should today ask whether starting a large pivotal programme is wise. At best one cenerimod dose has shown hints of activity, but first running a confirmatory phase 2 trial to test this hypothesis prospectively would be more prudent.

The Care study toplined today tested four doses of cenerimod, an S1P receptor modulator. The highest, 4mg, showed a numerical improvement in the primary endpoint, mSLEDAI-2K score versus placebo at six months, Idorsia said today without giving any further efficacy details apart from revealing a nominal p value of 0.029 for the 4mg dose.

Non-significant

On the face of it this does seem promising, even ignoring the fact that, given the statistical penalty for analysing the four doses separately, the p value was highly non-significant.

But seasoned biotech investors will be aware that any benefit reported in a mid-stage trial would be expected to wane in the stricter setting of phase 3. We do not know the absolute benefit shown by cenerimod 4mg, but even a nominal p of 0.029 is hardly an overwhelming signal of efficacy, and such a borderline effect would be expected to be at an especially high risk of melting away in a pivotal trial.

Moreover, Idorsia appears to be hinting that there is a numerical dose-response effect in Care, but importantly it has not actually spelled this out. If the highest dose has done best this is clearly good, but Idorsia has revealed nothing about the numerical performance of any of the lowest three cenerimod doses.

Idorsia says 4mg was also associated with improvements in several patient subpopulations, especially those with severe disease, and on the SLE responder index, a four-point composite measure of activity in lupus. It did not say whether either would be incorporated into the phase 3 programme it now aims to discuss with regulators.

Finally, if 4mg is so good, with no toxicity penalty, why not test an even higher dose? The disappointment is the second to hit Idorsia in recent weeks; in mid-October its Fabry disease project lucerastat failed a pivotal study.

MS mechanism

S1P modulation is more commonly associated with drugs for multiple sclerosis, including Novartis’s Gilenya and Mayzent, and Idorsia/J&J’s recently approved Ponvory. Another positive for cenerimod, which Idorsia describes as highly selective with a bias for the S1P1 subtype, is that it had no impact on blood pressure or pulmonary function, which S1P1 receptor modulators are known to affect.

Still, this mechanism has hardly proved a resounding success in lupus. According to Evaluate Pharma two other projects, the S1P1/4/5 agonist prodrug KRP-203 and the S1P1 receptor antagonist amiselimod, were once studied in the disease, but they have seen no work since 2017.

Cenerimod carried modest sellside revenue forecasts, $108m in 2026, according to Evaluate Pharma, but these were likely predicated on Care serving as one registrational study, and a single phase 3 sufficing as the other. There will now be a lengthy delay while Idorsia undertakes two new phase 3 tests, whose likelihood of success must now be seen as remote.

Selected lupus projects acting on S1P (sphingosine-1-phosphate)
Project	Company	Mechanism	Lupus summary	Other indications
Cenerimod	Idorsia	S1P1 receptor modulator	Moving to ph3 after failing ph2	None
Mocravimod (KRP-203)	Kyorin/Novartis	S1P1/4/5 agonist prodrug	Abandoned after ph2	Ph2 in ulcerative colitis terminated
Amiselimod (MT-1303)	Biogen/Mitsubishi Chemical	S1P1 receptor inhibitor	Abandoned after ph1	Ph2 in ulcerative colitis enrolling; ph2 in relapsing/remitting MS completed
Source: Evaluate Pharma & clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/trial-results/idorsia-sets-itself-failure

US FDA approval tracker: October

 Delays and complete response letters dominated the FDA regulatory scene last month, including a knockback for the troubled pain project tanezumab. After 16 years, and 39 clinical trials, Pfizer and Lilly finally scrapped the whole development programme. Elsewhere, Oncopeptide’s Pepaxto was withdrawn from the US market after the confirmatory Ocean study showed overall survival concerns. The drug had gained accelerated approved for fifth-line multiple myeloma in February. In better news for biopharma, the green light for Roche’s Tecentriq as an adjuvant therapy in NSCLC came early. However, the label restricts Tecentriq’s use to PD-L1-expressing stage II-IIIA patients, and data from the competition looms. Merck & Co’s Keynote-091 trial, testing Keytruda in in stage IB-IIIA patients regardless of PD-L1 expression, is expected to yield data soon.

Notable first-time US approval decisions in October
Project	Company	Indication(s)	2026e sales by indication ($m)	Outcome
Cibinqo (abrocitinib)	Pfizer	Atopic dermatitis	1,035	No decision yet
Bimzelx (bimekizumab)	UCB	Plaque psoriasis	992	Delayed (inability to conduct facility inspections because of travel restrictions)
Vynpenta (avacopan)	Chemocentryx	ANCA-associated vasculitis	610	Approved
DaxibotulinumtoxinA	Revance	Glabellar lines	430	CRL (manufacturing deficiencies)
FT218	Avadel	Narcolepsy	332	Delayed (no new date disclosed)
Narsoplimab (OMS721)	Omeros	Haematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)	298	CRL (additional data needed)
Scemblix (asciminib)	Novartis	3L chronic myeloid leukaemia	279	Accelerated approval (Philadelphia chromosome-positive CML in chronic phase) Full approval (with the T315I mutation)
Zimhi	Adamis	Opioid overdose	64	Approved (after two CRLs)
Mydcombi	Eyenovia	Pupil dilation agent	28	CRL (reclassified as a drug-device combination)
Raylumis (tanezumab)	Lilly/Pfizer	Osteoarthritis pain	24	CRL (negative adcom in March)
Rethymic (RVT-802)	Enzyvant, Sumitomo Dainippon Pharma	Paediatric patients with congenital athymia	16	Approved
Tyrvaya (OC-01)	Oyster Point	Dry eye disease	–	Approved
Xipere	Bausch Health/ Clearside	Macular oedema associated with uveitis	–	Approved
Kyzatrex	Marius	Primary and secondary male hypogonadism	–	No decision yet
Vuity (pilocarpine HCl ophthalmic solution 1.25%/ AGN-190584)	Abbvie	Presbyopia (age-related blurry near vision)	–	Approved
Source: Evaluate Pharma & company releases.

 

Advisory committee meetings in October
Project	Company	Indication	2026e sales by indication ($m)	Outcome
Comirnaty	Pfizer/Biontech	Covid vaccination in children aged 5-11	2,819	Recommended, given EUA on Oct 29
Spikevax	Moderna	Booster dose to individuals aged 65 and older, or at high risk owing to medical conditions or occupation	2,756	Recommended
Ad26.COV2-S	J&J	Booster dose to individuals aged 18 and older	767	Recommended
Pepaxto	Oncopeptides	In combination with dexamethasone for the treatment of adult patients with r/r multiple myeloma who have received at least four prior lines of therapy	552	Cancelled, Pepaxto withdrawn from US market (had accelerated approval)
Maribavir	Takeda	Adults with post transplant cytomegalovirus infection/disease	355	Recommended
Source: FDA ad com calendar & Evaluate Pharma.

 

Supplementary and other notable approval decisions in October
Product	Company	Indication (clinical trial)	Outcome
Tecartus	Gilead	Adult patients with r/r ALL (Zuma-3)	Approved
Dextenza	Ocular Therapeutix	Ocular itching associated with allergic conjunctivitis	Approved
Dupixent	Sanofi/ Regeneron	Asthma in ages 6-11 (Voyage)	Approved
Susvimo (Lucentis port delivery system)	Roche	Wet AMD (Archway)	Approved
Cortrophin Gel	ANI	Multiple sclerosis, rheumatoid arthritis, and nephrotic syndrome	Approved
Verzenio	Lilly	HR+ Her2- high risk early breast cancer (monarchE)	Approved
Keytruda	Merck & Co	1L cervical cancer plus chemo (whose tumours express PD-L1) also 2L as a single agent (Keynote-826)	Approved (2L converted to full approval from accelerated approval)
Tecentriq	Roche	Adjuvant treatment for adults with Stage II-IIIA NSCLC whose tumours express PD-L1≥1% (Impower-010)	Approved (~6 weeks early)
Biktarvy	Gilead	Low-dose tablet for HIV treatment in virologically suppressed children weighing at least 14 kg (Cohort 3)	Approved
Cyltezo (Humira biosimilar)	Boehringer Ingelheim	RA, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, polyarticular juvenile idiopathic arthritis	Approved as interchangeable biosimilar
Tyvaso DPI	Mannkind/United Therapeutics	PAH and pulmonary hypertension associated with interstitial lung disease (Breeze)	CRL (deficiencies at contract manufacturer)
Myring	Mayne Pharma/ Mithra	Generic contraceptive ring	CRL (additional data)
Xeljanz	Pfizer	Ankylosing spondylitis (A3921120)	No decision yet
Olumiant	Lilly	Atopic dermatitis (Breeze-AD program)	No decision yet
Rinvoq	Abbvie	Atopic dermatitis, psoriatic arthritis and ankylosing spondylitis	No decision yet
Andexxa	Astrazeneca	Addition of edoxaban and enoxaparin (FXa inhibitors) to the label	No decision yet
Source: Evaluate Pharma & company releases. https://www.evaluate.com/vantage/articles/news/snippets/us-fda-approval-tracker-october-1

No Evidence Found Of In-Game COVID-19 Transmission For SEC 2020 Football Season

 As the COVID-19 pandemic continued during fall 2020, athletic conferences and leagues had to make critical decisions about how sporting competitions would be played. Like other organizations, the Southeast Conference (SEC) set protocols to monitor, manage and mitigate COVID-19 exposure during athletic events.

Researchers at Texas A&M University recently analyzed contact tracing data recorded during official conference games and SEC testing data for athletes in play. They found that competition during the fall 2020 football season was relatively safe.

Between Sept. 26 and Dec. 19, 2020, a total of 1,190 players had 109,762 opposing player interactions over the 64 SEC regular season games. Benika Dixon and several other researchers at the Texas A&M University School of Public Health analyzed the data from these interactions and found that most of the interactions were fleeting.

“Although there are a lot of these interactions that happen during a football game, they tend to be very brief, with the majority of them being less than 26 seconds,” Dixon said. “We also looked at recurring interactions between players and, very similarly, found that total contact was brief as well. Most contacts that were recurring with two players were still less than 97 seconds.”

Only 13 opponent pairs had in-game contact that exceeded the Centers for Disease Control and Prevention’s 15-minute threshold for close contacts. Of those 13 pairs, none tested positive for COVID-19 in the 14 days prior to or after the game.

“For this particular paper, we looked at the player interaction, but we did not look at interactions that occurred between players and referees or players and coaches,” Dixon said. “We also looked strictly at gametime contact, so we didn’t take into consideration any contacts that may have happened pre- or post-game. I think there’s definitely an opportunity to expand on this research and look at other types of interactions that occur.”

The findings indicate that through the use of innovative strategies, infectious diseases such as COVID-19 can be prevented and monitored during sporting competitions. Dixon said this proves the importance of prevention protocol: “Gameplay was relatively safe when implementing strategies such as contact tracing, and overall, it showed the importance of utilizing protection strategies during athletics.”

“This study shows the importance of public health prevention strategies to allow athletic activities during an infectious disease pandemic,” said School of Public Health Dean Shawn Gibbs, who serves on the SEC Medical Task Force.

https://today.tamu.edu/2021/10/29/researchers-find-no-evidence-of-in-game-covid-19-transmission-for-sec-2020-football-season/

Federal contractors get broad flexibility to enforce Covid vaccine rules for millions of workers

 

• Federal contractors will have broad leeway to enforce President Biden’s Covid-19 vaccine mandate, according to guidance the White House released Monday.
• Under the new guidance, federal contractors from IBM to Boeing will have flexibility to determine how they enforce the vaccination requirements for workers who refuse to be vaccinated.
• Federal contractors including airlines like Southwest, American and aerospace giant Boeing have said employees must be vaccinated by the Dec. 8 deadline or apply for an exemption.

• Federal contractors will have broad leeway to enforce President Joe Biden’s Covid-19 vaccine mandate, according to new guidance the White House released Monday, laying out details on implementation of the rules.

  Under the new guidance, federal contractors from IBM and Boeing to food service providers will have flexibility to determine how they enforce the vaccination requirements for workers who refuse to be vaccinated.

  The federal contractor guidelines are stricter than the forthcoming vaccine mandate for businesses with 100 or more employees, which allow for regular testing broadly as an alternative to a vaccine. The Labor Department is still finalizing those rules. Businesses have asked for that mandate to be delayed until after the holiday season over concerns about possible supply chain disruptions.

  Senior administration officials made clear that Dec. 8 is not a hard deadline for contractors to have all of their employees fully vaccinated. Instead, contractors must demonstrate they are making a good faith effort to ensure employees are getting vaccinated and have plans in place to ensure masking and social distancing policies are followed in the workplace.

  Federal contractors won’t have to show proof of vaccination rates at the deadline, a senior administration official said. But noncompliance could result in the loss of a federal contract.

  Federal agencies could bar a contractor employee who refuses to be vaccinated from entering a federal workplace, according to the guidelines.

  “In most circumstances individuals who are not fully vaccinated need to follow applicable masking, physical distancing, and testing protocols,” the guidelines said.

  The federal government will defer to contractors to determine when an employee has a sincerely held religious belief or medical condition that requires accommodation, according to senior administration officials. Federal contractors are not required to make a final determination on accommodation requests when an employee begins work.

  “The covered contractor may still be reviewing requests for accommodation as of the time that covered contractor employees begin work on a covered contract or at a covered workplace,” the guidelines said.

  However, federal contractors must require employees with pending accommodation requests to abide by policies on masking and social distancing while their requests are under review, according to the guidelines.

  Federal contractors including some large airlines such as Southwest and American, and aerospace giant Boeing, have said employees must be vaccinated by the Dec. 8 deadline or apply for an exemption.

  Some labor groups have opposed the mandate, including pilots’ unions at American and Southwest. The latter sought to bar the implementation of the mandate, a request a federal judge in Texas denied last week.

  Eleven Republican-led states sued the administration on Friday, arguing the vaccine mandate is unconstitutional. The administration has made clear that the requirements supersede any state laws that bar compliance with Covid-19 mitigation policies.

• “A covered contractor should determine the appropriate means of enforcement with respect to its employee at a covered contractor workplace who refuses to be vaccinated and has not been provided, or does not have a pending request for, an accommodation,” said the guidelines, which affect millions of workers.

• The White House released the federal contractor guidance Monday after contractors sought more details on how to implement the rules. Biden issued an executive order on Sept. 9 requiring federal contractors to ensure their employees are vaccinated against Covid-19 and follow masking and social distancing policies. The administration set a Dec. 8 deadline for contractors to implement those requirements.

• American and Southwest executives have softened their tone over the mandate, urging employees to apply for religious or medical exemptions if they don’t plan to get the vaccine, and said they don’t expect to terminate employees over it. Southwest last month dropped a plan to put workers with pending exemption requests on unpaid leave. Airline executives said they don’t foresee the mandate impacting flights over the holidays.

• https://www.cnbc.com/2021/11/01/federal-contractors-will-have-broad-flexibility-to-enforce-covid-vaccine-rules.html

Theseus Pharma: FDA Clears Application for Treatment of Gastrointestinal Stromal Tumors

 Theseus Pharmaceuticals, Inc. ("Theseus"), a biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development and commercialization of transformative targeted therapies, today announced U.S. Food and Drug Administration (FDA) clearance of an investigational new drug (IND) application to evaluate THE-630, the company's lead development candidate, in patients with gastrointestinal stromal tumors (GIST). THE-630 is a pan-variant inhibitor of the receptor tyrosine kinase KIT designed for patients with advanced GIST whose cancer has developed resistance to earlier lines of therapy.

"The IND clearance for THE-630 marks an important milestone for Theseus as we transition into a clinical-stage company," said Tim Clackson, Ph.D., president and CEO of Theseus Pharmaceuticals. "Patients with previously-treated GIST often have tumors that have developed more than one mutation in KIT that causes resistance to treatment, and we believe treatment with a kinase inhibitor that is active against all relevant mutations—that is, a pan-variant inhibitor—is a promising approach to address this key mechanism of resistance. We look forward to initiating the Phase 1/2 clinical trial and evaluating the potential that THE-630 may offer for patients with advanced GIST who have developed resistance to prior therapy."

THE-630 exhibits potent in vitro activity against all known classes of KIT activating and resistance mutations in GIST. In preclinical studies, THE-630 achieved predicted pan-variant KIT inhibitory blood concentrations at tolerable doses and induced significant anti-tumor activity. Theseus plans to initiate a Phase 1/2 dose escalation and expansion clinical trial of THE-630 in patients with previously treated advanced GIST between late fourth quarter 2021 and mid-first quarter 2022.

https://www.biospace.com/article/releases/theseus-pharmaceuticals-announces-fda-clearance-of-investigational-new-drug-application-for-the-630-a-pan-variant-kit-inhibitor-in-development-for-the-treatment-of-gastrointestinal-stromal-tumors-gist-/

Teva's Risperidone Injectable Wards Off Schizophrenia Relapse in Phase III

 Teva Pharmaceuticals announced positive results from its Phase III trial on a subcutaneous, long-acting injectable risperidone formulation in the treatment of schizophrenia. 

The Phase III Risperidone Subcutaneous Extended-Release (RISE) study compared TV-46000/mdc-IRM, an injectable risperidone formulation, given once a month and once every two months with placebo in patients diagnosed with schizophrenia and have already taken risperidone for stabilization therapy. At week 24, the researchers found that those who took either the once-a-month or once-every-two-month doses experienced longer periods before relapsing. 

With that said, the primary endpoint of time to impending relapse was achieved, same with the number of patients who maintained their stable condition at week 24. Prolonged time to relapse was recorded at 3.5 and 5.0 times with TV-46000 and only 2.7 times with the placebo when observed at the 24th week. Its safety profile is also consistent with other risperidone formulations, and no new safety signals emerged. 

The researchers evaluated 1,267 patients aged 13 to 65 years old, 863 of whom were enrolled in the program, while the remaining 544 were randomized. The most common adverse reactions include weight gain, extrapyramidal disorder, and nasopharyngitis. 

Schizophrenia is a chronic and severe mental illness characterized by extreme distortions in emotions, perception, thinking, language, behavior, and sense of self. The average onset age is in the late teens to early 20s for males and late 20s to early 30s for females. There are around 20 million people diagnosed with it worldwide, and 70% of them are not receiving proper care despite the disease being treatable. 

Relapse rates range from 50% to 92%, and each relapse comes with a biological risk of loss of function, changes in brain morphology, and treatment resistance. To further complicate matters, most patients are not aware that they are ill, which is why there is a high non-adherence to treatment, high discontinuation rate, and high cost of healthcare. In the U.S. alone, around 3.5 million are diagnosed with the condition.

"It is crucial to provide patients and prescribers with treatment options that have the potential to reduce relapse rates to help manage and stabilize the disease over time. Coming off the heels of the recent FDA acceptance of our New Drug Application, we’re proud to be sharing our Phase III data at this year’s Psych Congress. We are committed to investigating the full potential of our subcutaneous long-acting injectable (LAI) formulation of risperidone for the treatment of this complex and burdensome illness," noted Eran Harary, M.D., the vice president global head of specialty R&D at Teva, in a statement. 

Teva Pharmaceuticals said it will continue to explore the drug's mechanisms, particularly its potential as a long-acting injectable. Details of the Phase III RISE study were presented at the 2021 Psych Congress Annual Meeting in Texas.

https://www.biospace.com/article/teva-pharmaceuticals-long-acting-risperidone-injectable-shows-promise-in-treating-schizophrenia/

Merck Delays Acceleron Deal Amidst Continuing Stakeholder Criticism

 One month after striking an $11.5 billion deal to acquire Acceleron Pharma, Merck temporarily withdraws its merger agreement to allow more time for review from the U.S. Federal Trade Commission and the U.S. Department of Justice.

Merck announced the temporary stay in the merger late Friday. The decision came after Avoro Capital Advisors, which owns a 7% stake in Acceleron, posted its objections to the deal. Avoro, which initially objected to the agreement following the announcement, reaffirmed that opposition last week. 

In an open letter released a day before Merck’s announcement, Avoro claimed that the merger agreement is not in the best interest of Acceleron shareholders. The financial company said the $180 per share value that Merck and Acceleron agreed to for the merger “drastically undervalues” the company. Avoro said that is just a 38% premium relative to the stock’s average closing price over the previous three months.

Avoro argued that Acceleron is close to a “value inflection point” regarding the company’s Phase III pulmonary arterial hypertension (PAH) drug sotatercept. The company believes Phase III data will be available by the end of 2022 and, if it is positive, then the potential approval of the drug should translate into a higher-per-share price for Acceleron’s stock. Perhaps as high as $250 per share. In 2019, sotatercept received Orphan Drug Designation for PAH from the FDA. 

“As we stated previously, we believe that Acceleron’s management team has done an excellent job creating value for shareholders until now and that the company has great potential as a standalone entity. We also believe Merck could ultimately be a great partner for XLRN. The problem is not the fit, it is both the timing and the price,” Avoro said in its letter.

Avoro Capital noted that some analysts have also suggested that the $180 per share price is too low. The firm pointed to Barclays Carter Gould, who suggested that Acceleron could get a higher premium prior to the inking of the deal. Jefferies Analyst Akash Tewari also called the $180 price ‘a bargain.” 

Rather than jump into a merger agreement with Merck, Avoro suggested that Acceleron remain an independent company. They pointed to the lack of other bidders for Acceleron, which means the idea of a sale is premature. 

Last month, a filing with the U.S. Securities and Exchange Commission revealed that Acceleron’s management had reached out to other companies regarding a deal after Merck initiated discussions. Primarily, Acceleron reached out to Bristol Myers Squibb, which owns about 11% of Acceleron. 

BMS and Acceleron jointly developed the blockbuster drug Reblozyl, which was approved in 2019 for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. BMS balked at acquiring Acceleron, the filing shows. 

In its statement Friday, Merck has temporarily agreed to stay on its merger to allow time for the government to review the merger agreement. There is potential for a conflict due to Merck’s existing PAH pipeline, including Adempas, which it gained in a licensing deal with Bayer. 

Earlier this year, Merck initiated a Phase II/III PAH study of MK-5475, an inhaled soluble guanylate cyclase (sGC) stimulator. The government may request Merck divest the experimental drug. 

Merck could refile its merger agreement as early as today and anticipate that the deal could still close by the end of 2021. 

https://www.biospace.com/article/merck-delays-acceleron-deal-to-allow-time-for-government-review-while-stakeholder-presses-claim/