FDA declares Pepcid, Nexium and others free of NDMA contamination

The bad news for heartburn sufferers, of course, is that Zantac and its ranitidine generics have, perhaps for years, contained a suspected carcinogen without the FDA knowing it. The good news is that the FDA has now declared a handful of branded antacid alternatives and their generics as safe for consumers.

The FDA Wednesday said that preliminary tests of alternatives including Pepcid (famotidine), Tagamet (cimetidine), Nexium (esomeprazole), Prevacid (lansoprazole) and Prilosec (omeprazole) found no N-nitrosodimethylamine (NDMA), the suspected cancer-causing agent found in OTC ranitidine drugs including the popular Zantac.

The announcement came as the agency said more Zantac generic makers are voluntarily calling their meds. Dr. Reddy’s Laboratories confirmed that NDMA had been found in its ranitidine products, and Perrigo has joined the recall after testing its versions.

The recent discovery of NDMA in Zantac and its generics came after the finding last year that the impurity was being created during the manufacturing of many high blood pressure drugs like losartan and valsartan.

The online pharmacy Valisure, which tests all of the products it sells, notified the FDA earlier this year that it had found a similar manufacturing phenomenon was occurring in ranitidine drugs. Valisure filed a citizen petition seeking to have the FDA have drugmakers recall the suspected products, set an acceptable NDMA level and create tests for the suspected carcinogen.

While the FDA has rejected Valisure’s testing methods, the agency has set standards and informed drugmakers how to test for NDMA in ranitidine. It announced Wednesday a new test using what it called “a more widely available technology than the first posted method.”

https://www.fiercepharma.com/manufacturing/need-a-safe-antacid-for-heartburn-fda-declares-pepcid-nexium-and-others-free-ndma

Diagnostics specialists win the US device approval race

The speediest device developer is Roche, but a look at companies’ strategies shows the perils of relying on bought-in tech.

Roche is notorious among the large medical device and diagnostic developers for the speed at which its innovative products gain FDA approval. The company’s medical technologies are exclusively in vitro diagnostics (IVDs), and these tend to pass through the regulatory process rapidly, being relatively simple and posing few risks to the patient.
But an analysis of innovative device approvals over the past five years shows that Roche’s applications are granted even more rapidly than IVDs in general – more than three months faster, on average.
Partly this can be put down to experience. Roche obtained 20 FDA approvals for innovative devices between 2014 and the end of September 2019, many of which are run on established instruments and therefore require minimal investigation. Companies that do not make such regular submissions, or that go to regulators with less well-characterised technologies, will naturally take longer.
The slowest IVD approval of 2019, for example, was that of the Sangia prostate specific antigen blood test developed by Opko Health; this took 14.8 months. Opko is a diversified company, and its lack of specialism in IVDs might have contributed to the relative lag.
A look at the cohort with the most approvals over the past five years shows how much of a lead Roche has opened up over its rivals.
The table below includes only those companies with more than five innovative device approvals – first-time PMAs, humanitarian device exemptions and de novo 510(k) clearances – in the five-year period.

Innovative device approvals 2014-19* by company strategy
Company	Number of approvals	Avg approval time (mth)	% developed in-house	Avg approval time in-house (mth)	Avg approval time bought in (mth)
Roche	20	7.4	90%	7.6	5.8
Medtronic	17	15.4	94%	13.7	14.0
Abbott Laboratories	16	22.3	69%	14.2	40.2
Boston Scientific	15	11.2	80%	12.2	7.1
Becton Dickinson	10	11.3	10%	17.7	10.6
Stryker	8	15.6	25%	10.2	17.4
Qiagen	7	11.1	100%	11.1	–
Asahi Kasei	6	24.8	33%	14.7	29.9
Johnson & Johnson	5	22.4	60%	25.0	18.5
Biotronik	5	12.3	100%	12.3	–
Cook Group	5	14.0	100%	14.0	–
Edwards Lifesciences	5	13.0	100%	13.0	–
Average		14.4		12.6	18.7
*2019 figure includes approvals up to Sep 30. Source: EvaluateMedTech.

The second fastest after Roche is Qiagen, which also specialises in IVDs. The group has been in trouble for some time, with its efforts to break into next-generation sequencing having misfired (Storm-tossed Qiagen plots a course to higher growth, October 8, 2019). At least its approach to regulatory affairs seems to bear fruit.
In and out
As well as the differences between the companies, interesting enough in themselves, it is worth examining their strategies when it comes to buying in new devices. Roche develops almost all its products in house, but two of its 20 approvals were applied for by a different company that Roche subsequently acquired – Foundation Medicine – and both were approved in less than six months.
Some groups have made a success, from a regulatory standpoint, of their acquisitions. Boston Scientific has bought an astonishing 27 companies since the beginning of 2014, and the devices resulting from those deals were approved five months faster, on average, than those resulting from its own R&D labs.
But relying on bought-in technologies is a hit-and-miss strategy. The 31% of approved devices Abbott gained from acquisitions took more than two years longer, on average, to get their green lights than those it developed organically. Abbott’s slowest was the Amplatzer VSD occluder, a catheter-based device intended for closure of post-heart attack muscular ventricular septal defects, which was granted a human device exemption nine and a half years after its originator, Aga Medical, filed it.
Asahi Kasei’s inorganic products have also been slow to gain the FDA’s blessing. One example is its ResQCPR System, a non-invasive therapy to boost blood circulation in patients with non-traumatic cardiac arrest. This was approved nearly four years after its initial developer, Advanced Circulatory Systems, which was bought by Asahi Kasei in 2014, submitted it.
The speed of likely approvals is probably not the foremost consideration to occupy a group mulling a takeover – the size of the market and forecast sales for the target’s devices would probably be of more consequence, with buyers happy to wait for the FDA’s nod provided the return is great enough. Sooner, however, is undeniably better than later.

Innovative device approvals 2014-19* by therapy area
Therapy area	Number of approvals	Avg approval time (mth)
In vitro diagnostics	106	10.5
Cardiology	92	14.5
Neurology	39	15.4
Orthopaedics	23	24.8
General & plastic surgery	17	16.1
Ophthalmics	17	13.0
Diabetic care	16	10.7
Gastroenterology	16	12.7
Anaesthesia & respiratory	12	14.2
Average		13.8
*2019 figure includes approvals up to Sep 30.Source: EvaluateMedTech.

https://www.evaluate.com/vantage/articles/data-insights/other-data/diagnostics-specialists-win-us-device-approval-race

Astra guns for quick cancer and lupus filings

Questions about clinical data aside, Imfinzi and tremelimumab could be filed for first-line lung cancer by the end of the year.

This week’s surprisingly positive readout of Bristol-Myers Squibb’s Checkmate-9LA study put the spotlight on Astrazeneca’s similar Poseidon trial. Today the UK group confirmed that, despite an apparent timeline slippage, should Poseidon read out positively it would be used for a US approval filing before the end of the year.
Remarkably, the basis for such a filing will be progression-free survival, a possibly tall order in a first-line lung cancer setting already well served by an approved drug, Merck & Co’s Keytruda. Astra was also remarkably bullish about its lupus project anifrolumab, which it wants to file even though only one of its two pivotal trials worked.
Either way, the lung cancer submission is expected to come first. Doubts around Astra’s first-line NSCLC strategy had arisen because Poseidon’s clinicaltrials.gov entry was changed in August to reflect a new planned primary completion date: April 2021 instead of September 2019.
But on Astra’s third-quarter call today José Baselga, vice-president of oncology R&D, stated: “The results of Poseidon are expected in the fourth quarter of this current year. What we will have … is the final PFS analysis; the expected analysis for final OS is going to come later, in 2021.”
Poseidon tests four cycles of chemo on top of Imfinzi with or without tremelimumab, versus chemo alone, and has OS and PFS as co-primary endpoints. The clear implication from Astra’s timeline, therefore, is that the company thinks PFS alone will be sufficient for a regulatory filing in first-line NSCLC.
Even if, as expected, such a filing is made in all-comers, such patients already have the option of Keytruda’s chemo combo, backed by OS data from the Keynote-189 trial. And Bristol might soon file its Imfinzi/Yervoy/chemo triplet in this setting, backed by an apparently positive OS hit in Checkmate-9LA (Bristol might play a role in front-line lung cancer after all, October 23, 2019).
As such it could be asking a lot to expect the US FDA to wave Astra’s combo through on the strength of PFS alone, the risk being that the agency will first want to see full OS data from Poseidon. Mr Baselga refused to say whether Bristol’s Checkmate-9LA success had influenced Astra’s view on Poseidon’s analysis or chances of success.
It’s lupus
Meanwhile, in lupus, where Astra recently scored a win with anifrolumab, the group could be on safer ground, given that apart from Glaxosmithkline’s Benlysta nothing new has come to market recently.
Still, anifrolumab’s pivotal success came in one study, Tulip-2, which had been overhauled based on the failure of a first phase III trial, Tulip-1. And the success was due to the use of a lupus measure called BICLA, an endpoint of which the FDA’s view is not entirely clear (Second time lucky for Astra in lupus, August 29, 2019).
But today Mene Pangalos, Astra’s vice-president of biopharmaceutical R&D, was unambiguous, stating: “BICLA is a regulatory-approved endpoint.” He also said that if Tulip-1 was analysed post-hoc according to BICLA it too would yield a positive result, so the issue is more subtle than simply asking for approval on the basis of a single phase III trial.
“We have two phase III studies – one positive with BICLA, one positive in a post-hoc analysis – and we also have a very large phase II study that also was positive,” said Mr Pangalos. A US filing is planned for the second half of next year.
Given the unmet need this could give anifrolumab a good shot at approval – an argument that is more difficult to make for Imfinzi/tremelimumab in NSCLC.
https://www.evaluate.com/vantage/articles/news/astra-guns-quick-cancer-and-lupus-filings

Investors cheer latest Rigel business update

Shares of Rigel Pharmaceuticals (NASDAQ:RIGL) gained over 10% today after the company announced a business update highlighting recent areas of progress. The small-cap pharma told investors that third-quarter 2019 revenue for its only drug product, Tavalisse, is expected to come in at about $11.7 million. That’s actually a little below the average Wall Street expectation of $11.9 million, according to numbers compiled by Yahoo! Finance.
But it’s close enough, and somewhat eases concerns over the drug’s sluggish launch. Perhaps more important, Rigel announced that its pipeline — another concern — is suddenly buzzing with activity. The company completed a phase 1 trial for its lead wholly owned drug candidate and announced an entirely new branch of its pipeline that had never before been known to investors. The first drug candidate from this new focus has already started a phase 1 clinical trial.
Rigel fell out of favor with investors after Tavalisse, a treatment for a rare blood disorder characterized by a shortage of platelets, got off to a brutally slow start. Analysts thought the drug could reach peak annual sales of $300 million, but it’s on pace for just $40 million in full-year 2019 revenue. Perhaps it’s a sign of impatience, but the stock has fallen 20% since the beginning of the year.
The recent update provides some hope that Tavalisse is getting back on track. The unofficial $11.7 million figure would translate to a 15% quarter-over-quarter increase, up from recent 10% sequential growth clips.
The update also shows that Rigel Pharmaceuticals is continuing to invest in its future. The company’s pipeline has four unique drug candidates partnered with four different collaborators, but only had one wholly owned asset before today. That asset, R835, inhibits interleukin receptor associated kinase 1 (IRAK1) and IRAK4. It could treat inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, and lupus. It successfully wrapped up a phase 1 trial.
And now R835 finally has some company. Rigel announced that it’s developing new drug candidates that inhibit receptor-interacting protein kinase 1 (RIP1, or sometimes referred to as RIPK1), led by R552. Investors may have never heard of RIP1, but it’s an increasingly hot area of research. The protein plays an important role in a number of inflammatory diseases, notably with strong links to Alzheimer’s and multiple sclerosis. And some RIP1 inhibitors can easily cross the blood-brain barrier. That makes it an intriguing target for new drugs — and the company appears to be one of the first to enter clinical trials.

It’s encouraging to see the company’s lone drug product accelerate revenue growth, and especially good to see the pipeline buzzing with activity. It’s a little too soon to get excited over R835 or R552, but they could provide Rigel with a first-mover advantage in partnering activities depending on early stage clinical results. That said, even with today’s pop, Rigel Pharmaceuticals is valued at just $300 million, so investors must remain mindful of the inherent risks of investing in small-cap pharmaceutical stocks.
https://www.fool.com/investing/2019/10/23/heres-why-rigel-pharmaceuticals-jumped-as-much-as.aspx

JPMorgan Downgrades Walgreens: Near-Term Growth Likely To Stay Challenged

Walgreens Boots Alliance Inc WBA 0.31% is scheduled to announce its fiscal fourth-quarter results on Oct. 28.
The company is likely to record a high-single digit decline in fiscal 2019 and its adjusted operating profit growth may remain under pressure in the near term, according to JPMorgan.

The Analyst

JPMorgan’s Lisa Gill downgraded Walgreens Boots Alliance from Overweight to Neutral, establishing a price target of $63.

The Thesis

Walgreens is taking longer to realize growth under its current strategy, and Gill said there is lack of clarity into the roadmap to improvement and limited catalysts in the near term.

Management had expressed optimism in delivering mid- to high-single digit growth in adjusted earnings per share. The analyst mentioned, however, there is limited clarity into the timing and key milestones in achieving this target.
Gill expects the company to report fourth-quarter adjusted earnings at $1.41 per share, meeting the consensus estimate. While gross margins may continue to contract, focus would be on signs of the trend improving versus recent quarters.
The analyst lowered the fiscal 2020 earnings estimate from $5.98 per share to $5.93 per share. Expecting the stock to remain “a show-me story” in fiscal 2020, Gill wrote that there are “better opportunities for upside in other companies within our coverage universe at the current time.”
https://www.benzinga.com/analyst-ratings/analyst-color/19/10/14645456/jpmorgan-downgrades-walgreens-says-near-term-growth-likely-to-remain-challenged

Immunomedics’ Long Wait For Redemption

Immunomedics, Inc. IMMU 0.19% is a biopharma company focusing on the development of antibody-drug conjugates, or ADCs.
The Morris Plains, New Jersey-based company was founded in 1982 and has yet to market a commercial product.
Its investigational therapies include ADCs that are designed to deliver a specific payload of chemotherapeutic agents directly to a tumor, and in the process reduce toxicities that are usually associated with the conventional administration of these agents.

The Pipeline

Immunomedics’ lead compound is sacituzumab govitecan, or IMMU-132, which is being evaluated as a monotherapy and in combination for multiple solid tumor types.

Failed First Attempt

Sacituzumab is in the most advanced stage of clinical development for treating patients with metastatic triple negative breast cancer, or mTNBC.
On July 18, 2018, the FDA accepted the BLA for the regulatory review of sacituzumab govitecan as a treatment option for mTNBC in the third-line setting and above, fixing the PDUFA action date at Jan. 18, 2019.
The breakthrough the company waited 37 long years for was not to be, as the FDA handed down a Complete Response Letter one day before the decision date.
The CRL pertained to chemistry, manufacturing and control issues, and the regulatory agency did not require any additional clinical or preclinical data, according to the company.
In the wake of the FDA snub, Immunomedics CEO and President Michael Pehl resigned in February of this year. The company also announced a slew of other management changes in its fourth-quarter earnings report, released in late February.
In April, Chief Medical Officer Rob Iannone announced his resignation.
In early February, Immunomedics disclosed an FDA establishment inspection report about a data integrity breach that occurred in February 2018, the scope of which included manipulation of bioburden samples, misrepresentation of an integrity test procedure in the batch record and backdating of batch records, including the dates of analytical results.
The findings were based on a pre-approval inspection conducted by the FDA at the company’s Morris Plains facility that occurred Aug. 6-14, 2018.
The FDA said it would complete a re-inspection of the facility as part of its regulatory review.

Source: Immunomedics
Immunomedics faced another setback in late September when it presented at ESMO 2019 with interim data from Cohort 1 of the Phase 2 TROPHY-U-01 trial that is evaluating sacituzumab in third line plus advanced unresectable/metastatic UC.
The efficacy data presented was inferior to enfortumab vedotin, or EV-103, which is being co-developed by Seattle Genetics, Inc. SGEN 0.63% and ASTELLAS PHARMA/ADR ALPMY 2.11%.
Analysts said there is room for both candidates.
“Both drugs will play important roles in this landscape,” Piper Jaffray analyst Joseph Catanzaro said in a note reviewing the ESMO presentation.

The Rest Of The Pipeline

Labetuzumab govitecan, or IMMU-130, involves the anti-CEACAM5 antibody labetuzumab conjugated to SN-38 and is being studied for colorectal cancer.
A third ADC is a SN-38 conjugated form of IMMU-114, a humanized antibody against an immune response target, HLA-DR. It is being evaluated for hematologic cancers.

Collaborations, Partnerships

The company has ongoing collaborations with AstraZeneca plc AZN 5.32% to investigate sacituzumab in combination with the latter’s checkpoint inhibitors in earlier lines of therapy for mTNBC, advanced UC and metastatic non-small cell lung cancer, or mNSCLC.
Immunomedics is also working with Clovis Oncology Inc CLVS 2.34% on using the latter’s PARP inhibitor rucaparib in mTNBC, advanced UC and ovarian cancer.
The company is collaborating on a new Phase 1b/2 study sponsored by Massachusetts General Hospital that is evaluating sacituzumab in combination with Pfizer Inc. PFE 1.13%‘s PARP inhibitor talazoparib in patients with mTNBC previously treated with no more than one prior therapeutic regimen for metastatic disease.
The biopharma also has a collaboration agreement with Johnson & Johnson JNJ 0.54%‘s Janssen unit for the promotion of the recently approved Balversa. The drug is intended to treat adult patients with locally advanced or metastatic urothelial carcinoma that has a type of susceptible genetic alteration known as FGFR3 or FGFR2, and that has progressed during or following prior platinum-containing chemotherapy.
Immunomedics struck an exclusive license agreement with C-Bridge Capital-backed Everest Medicines II Limited to develop, register and commercialize sacituzumab govitecan in Greater China, South Korea and certain Southeast Asian countries.
For the outlicensing, the company received an upfront payment of $65 million, with an additional $60 million due on FDA approval and up to $710 million in development and sales milestone payments.

Market Potential

Immunomedics sees the third-line setting in mTNBC as a lucrative opportunity, with 8,000 patients in the U.S. and about 14,000 patients in the EU5 and Japan.
Second-line HR+/HER2- metastatic breast cancer patients number about 24,000 to 26,000 in the U.S., the company said.
About 19,000-22,000 second-line metastatic NSCLC patients are in the U.S., while the second-line setting for advanced ulcerative colitis presents another 13,000 to 15,000 patients.

Upcoming Catalysts

• BLA re-filing for sacituzumab govitecan in 3L+ mTNBC: late November or early December.
• Completion of enrollment of patients in the TROPHY U-01 study in UC: end-of-year 2019.
• Top-line data readout from the ASCENT study evaluating sacituzumab govitecan in the third-line setting of mTNBC: mid-2020.

Financials

Immunomedics reported revenue of $2.16 million and a loss of $273.84 million for the fiscal year ended June 30, 2018.
With the company opting to change its fiscal year to align with the calendar year beginning in 2019, as part of a transition report, it reported no revenue and a loss of $157.67 million for the six months ended Dec. 31, 2018.
For the three months ended June 30, 2019, the company did not report any revenue, versus $386,000 in revenue the same period last year. That figure was comprised of $250,000 in license fees and other revenue and $136,000 in R&D revenue.
The loss for the quarter narrowed from 68 cents per share to 40 cents per share, with the year-ago results weighed down by interest expenses of $58.86 million.
As of June 30, 2019, the company had cash and cash equivalents as well as marketable securities of $432.65 million compared to $497.80 million as of Dec. 31, 2018.

Stock Take

Immunomedics shares have gained about 8% year-to-date.
H.C. Wainwright analyst Raghuram Selvaraju has a Buy rating on Immunomedics with a $26 price target. The valuation was reached using a discounted cash flow-based assessment.
Selvaraju estimates a risk-adjusted enterprise value of $4.9 billion to IMMU-132 across all indications.
Piper Jaffray has an Overweight rating and $20 price target, and B Riley FBR has a Buy rating and $28 price target.
https://www.benzinga.com/general/biotech/19/10/14630054/biotech-stock-on-the-radar-immunomedics-long-wait-for-redemption

SpringWorks launches mid-stage study of mirdametinib in nerve tumors

Dosing is underway in a Phase 2b clinical trial, RENEU, evaluating SpringWorks Therapeutics’ (SWTX -3.5%) MEK inhibitor mirdametinib in pediatric and adult patients with neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (NF1-PN) (non-cancerous nerve tumors).

The primary endpoint of the open-label 100-subject study is response rate up to month 24. The estimated completion date is July 2022.

https://seekingalpha.com/news/3509140-springworks-launches-mid-stage-study-mirdametinib-nerve-tumors